thesis topics for nanomaterials

Nanomaterials: a review of synthesis methods, properties, recent progress, and challenges

First published on 24th February 2021

Nanomaterials have emerged as an amazing class of materials that consists of a broad spectrum of examples with at least one dimension in the range of 1 to 100 nm. Exceptionally high surface areas can be achieved through the rational design of nanomaterials. Nanomaterials can be produced with outstanding magnetic, electrical, optical, mechanical, and catalytic properties that are substantially different from their bulk counterparts. The nanomaterial properties can be tuned as desired via precisely controlling the size, shape, synthesis conditions, and appropriate functionalization. This review discusses a brief history of nanomaterials and their use throughout history to trigger advances in nanotechnology development. In particular, we describe and define various terms relating to nanomaterials. Various nanomaterial synthesis methods, including top-down and bottom-up approaches, are discussed. The unique features of nanomaterials are highlighted throughout the review. This review describes advances in nanomaterials, specifically fullerenes, carbon nanotubes, graphene, carbon quantum dots, nanodiamonds, carbon nanohorns, nanoporous materials, core–shell nanoparticles, silicene, antimonene, MXenes, 2D MOF nanosheets, boron nitride nanosheets, layered double hydroxides, and metal-based nanomaterials. Finally, we conclude by discussing challenges and future perspectives relating to nanomaterials.

1. Introduction

The term nanometer was first used in 1914 by Richard Adolf Zsigmondy. 5 The American physicist and Nobel Prize laureate Richard Feynman introduced the specific concept of nanotechnology in 1959 in his speech during the American Physical Society's annual meeting. This is considered to be the first academic talk about nanotechnology. 5 He presented a lecture that was entitled “There's Plenty of Room at the Bottom”. During this meeting, the following concept was presented: “why can’t we write the entire 24 volumes of the Encyclopedia Britannica on the head of a pin?” The vision was to develop smaller machines, down to the molecular level. 6,7 In this talk, Feynman explained that the laws of nature do not limit our ability to work at the atomic and molecular levels, but rather it is a lack of appropriate equipment and techniques that limit this. 8 Through this, the concept of modern technology was seeded. Due to this, he is often considered the father of modern nanotechnology. Norio Taniguchi might be the first person who used the term nanotechnology, in 1974. Norio Taniguchi stated: “nano-technology mainly consists of the processing of, separation, consolidation, and deformation of materials by one atom or one molecule.” 5,9 Before the 1980s, nanotechnology remained only an area for discussion, but the concept of nanotechnology was seeded in the minds of researchers with the potential for future development.

The invention of various spectroscopic techniques sped up research and innovations in the field of nanotechnology. IBM researchers developed scanning tunneling microscopy (STM) in 1982, and with STM it became feasible to attain images of single atoms on “flat” ( i.e. , not a tip) surfaces. 10 Atomic force microscopy (AFM) was invented in 1986, and it has become the most crucial scanning probe microscope technique. 11 The motivation to develop hard discs with high storage density stimulated the measurement of electrostatic and magnetic forces. This led to the development of Kelvin-probe-, electrostatic-, and magnetic-force microscopy. 12 Currently, nanotechnology is rapidly evolving and becoming part of almost every field related to materials chemistry. The field of nanotechnology is evolving every day, and now powerful characterization and synthesis tools are available for producing nanomaterials with better-controlled dimensions.

Nanotechnology is an excellent example of an emerging technology, offering engineered nanomaterials with the great potential for producing products with substantially improved performances. 13 Currently, nanomaterials find commercial roles in scratch-free paints, surface coatings, electronics, cosmetics, environmental remediation, sports equipment, sensors, and energy-storage devices. 14 This review attempts to provide information in a single platform about the basic concepts, advances, and trends relating to nanomaterials via covering the related information and discussing synthesis methods, properties, and possible opportunities relating to the broad and fascinating area of nanomaterials ( Scheme 1 ). It is not easy to cover all the literature related to nanomaterials, but important papers from history and the current literature are discussed in this review. This review provides fundamental insight for researchers, quickly capturing the advances in and properties of various classes of nanomaterials in one place.

2. Descriptions of terms associated with nanomaterials

3. approaches for the synthesis of nanomaterials, 3.1. top-down approaches.

The conditions under which arc discharge takes place play a significant role in achieving new forms of nanomaterials. The conditions under which different carbon-based nanomaterials are formed via the arc discharge method are explained in Fig. 6 . Various carbon-based nanomaterials are collected from different positions during the arc discharge method, as their growth mechanisms differ. 44 MWCNTs, high-purity polyhedral graphite particles, pyrolytic graphite, and nano-graphite particles can be collected from either anode or cathode deposits or deposits at both electrodes. 46–48 Apart from the electrodes, carbon-based nanomaterials can also be collected from the inner chamber. Different morphologies of single-wall carbon nanohorns (SWCNHs) can be obtained under different atmospheres. For example, ‘dahlia-like’ SWCNHs are produced under an ambient atmosphere, whereas ‘bud-like’ SWCNHs are generated under CO and CO 2 atmospheres. 49 The arc discharge method can be used to efficiently achieve graphene nanostructures. The conditions present during the synthesis of graphene can affect its properties. Graphene sheets prepared via a hydrogen arc discharge exfoliation method are found to be superior in terms of electrical conductivity and have good thermal stability compared to those obtained via argon arc discharge. 50

3.2. Bottom-up approaches

The hard template method is also called nano-casting. Well-designed solid materials are used as templates, and the solid template pores are filled with precursor molecules to achieve nanostructures for required applications ( Fig. 10 ). 78 The selection of the hard template is critical for developing well-ordered mesoporous materials. It is desirable that such hard templates should maintain a mesoporous structure during the precursor conversion process, and they should be easily removable without disrupting the produced nanostructure. A range of materials has been used as hard templates, not limited to carbon black, silica, carbon nanotubes, particles, colloidal crystals, and wood shells. 85 Three main steps are involved in the synthetic pathway for obtaining nanostructures via templating methods. In the first step, the appropriate original template is developed or selected. Then, a targeted precursor is filled into the template mesopores to convert them into an inorganic solid. In the final step, the original template is removed to achieve the mesoporous replica. 86 Via using mesoporous templates, unique nanostructured materials such as nanowires, nanorods, 3D nanostructured materials, nanostructured metal oxides, and many other nanoparticles can be produced. 87 From this brief discussion, it can be seen that a wide range of unique structured nanomaterials can be produced using soft and hard template methods.

4. Unique nanomaterial features

The electronic properties of semiconductors in the 1–10 nm range are controlled by quantum mechanical considerations. Thus, nanospheres with diameters in the range of 1–10 nm are known as quantum dots. The optical properties of nanomaterials such as quantum dots strongly depend upon their shape and size. 96 A photogenerated electron–hole pair has an exciton diameter on the scale of 1–10 nm. Thus, the absorption and emission of light by semiconductors could be controlled via tuning the nanoparticle size in this range. However, in the case of metals, the mean free path of electrons is ∼10–100 nm and, due to this, electronic and optical effects are expected to be observed in the range of ∼10–100 nm. The colors of aqueous solutions of metal nanoparticles can be changed via changing the aspect ratio. Aqueous solutions of Ag NPs show different colors at different aspect ratios. A red shift in the absorption band appears with an increase in the aspect ratio ( Fig. 12 ). 21

Among a range of unique properties, the following key properties can be obtained upon tuning the sizes and morphologies of nanomaterials.

4.1. Surface area

4.2. magnetism, 4.3. quantum effects, 4.4. high thermal and electrical conductivity, 4.5. excellent mechanical properties, 4.6. excellent support for catalysts, 4.7. antimicrobial activity.

Overall, these features have made nanoscale materials valuable for a wide range of applications, substantially boosting the performances of various devices and materials in a number of fields. Details of various nanomaterials, their properties, and applications in various fields will be discussed below.

5. Nanomaterials, characteristics, and applications

5.1. special carbon-based nanomaterials.

In the carbon-based nanomaterial family, fullerenes were the first symmetric material, and they provided new perspectives in the nanomaterials field. This led to the discovery of other carbon-based nanostructured materials, such as carbon nanotubes and graphene. 110 Fullerenes are present in nature and interstellar space. 111 Interestingly, fullerenes were the molecule of the year in 1991 and attracted the most research projects compared to other scientific subjects during that period. 112 Fullerenes possess several unique features that make them attractive for applications in different fields. Fullerenes display solubility to some extent in a range of solvents, and these characteristics make them unique compared to the other allotropes of carbon. 108

The chemical modification of fullerenes is an exciting subject, improving their effectiveness for applications. There are two main ways to modify fullerenes: 113 fullerene inner-space modification, and fullerene outer-surface modification.

Endohedral and exohedral doping examples are shown in Fig. 13 . 114 Fullerenes are hollow cages, and the interior acts as a robust nano-container for host target species when forming endohedral fullerene. 115 Endohedral fullerenes do not always follow the isolated pentagon rule (IPR). 116 To date, fullerene nanocages have received substantial consideration in the materials chemistry field due to their useful potential applications. Neutral and charged single atoms in free space are highly reactive and unstable. In the confined environment of fullerenes, these reactive species can be stabilized; for example, the LaC 60 + ion does not react with the NH 3 , O 2 , H 2 , or NO. Thus, reactive metals can be protected from the surrounding environment by trapping them inside fullerene cages. 117 Another emerging carbon nanomaterial is endohedral fullerene containing lithium (Li@C 60 ). 118 Lithium metal is very reactive, and extreme controlled environmental conditions are required to preserve or use it. In other words, secure structures are required for lithium storage. Li-Based endohedral fullerene shows unique solid-state properties. The encapsulation of lithium atoms in fullerene helps to protect lithium atoms from external agents. Li-Based endohedral fullerenes have the potential to open the door to nanoscale lithium batteries. 119 For the development of endohedral metallofullerenes, larger fullerenes are generally required, as they possess large cages to accommodate lanthanide and transition metal atoms more smoothly. 118 Fullerene nanocages are useful for the storage of gases. Fullerene is under consideration for hydrogen storage. 120,121

Exohedral fullerenes carry more potential for applications as outer surfaces can be more easily modified or functionalized. The exohedral doping of metals into fullerenes strongly affects the electronic properties via shifting electrons from the metal to the fullerene nanocage. 122 The practical application of fullerenes can be achieved with tailor-made fullerene derivatives via chemical functionalization. As fullerene chemistry has matured, a wide range of functionalized fullerenes has been realized through simple synthetic routes. 123 The combination of hydrogen-bonding motifs and fullerenes has allowed the modulation of 1D, 2D, and 3D fullerene-based architectures. 124 The excellent electron affinities of fullerenes have shown great potential for eliminating reactive oxygen species. The presence of excess reactive oxygen species can cause biological dysfunction or other health issues. The surfaces of fullerenes have been functionalized via mussel-inspired chemistry and Michael addition reactions for the fabrication of C 60 –PDA–GSH. The developed C 60 –PDA–GSH nanoparticles demonstrated excellent potential for scavenging reactive oxygen species. 125

Amphiphiles have great importance in industrial processes and daily life applications. Amphiphilic molecules consist of hydrophilic and hydrophobic parts, and they perform functions in water via forming two- and three-dimensional assemblies. Recently, conical fullerene amphiphiles 126 have emerged as a new class of amphiphiles, in which a nonpolar apex is supplied by fullerenes and a hydrophilic part is achieved through functionalization. The selective functionalization of the fullerene on one side helps to achieve a supramolecule due to unique interfacial behavior. The unique supramolecular structure formed via the spontaneous assembly of one-sided selectively functionalized fullerenes through strong hydrophobic interactions between the fullerene apexes and polar functionalized portions is soluble in water. Conical fullerene amphiphiles are mechanically robust. Via upholding the structural integrity, conical fullerene amphiphiles can be readily aggregated with nanomaterials and biomolecules to form multicomponent agglomerates with controllable structural features. 127 Fullerenes, after suitable surface modification, have excellent potential for use in drug delivery, but there have only been limited explorations of their drug delivery applications. 128,129 Fullerene-based nano-vesicles have been developed for the delayed release of drugs. 130 Water-soluble proteins have great potential in the field of nanomedicine. The water-soluble cationic fullerene, tetra(piperazino)[60] fullerene epoxide (TPFE), has been used for the targeted delivery of DNA and siRNA specifically to the lungs. 131 For diseases in lungs or any other organ, efficient treatment requires the targeted delivery of active agents to a targeted place in the organ. The accumulation of micrometer-sized carriers in the lung makes lung-selective delivery difficult, as this may induce embolization and inflammation in the lungs. Size-controlled blood vessel carrier vehicles have been developed using tetra(piperazino)fullerene epoxide (TPFE). TPFE and siRNA agglutinate in the bloodstream with plasma proteins and, as a result, micrometer-sized particles are formed. These particles clog the lung capillaries and release siRNA into lungs cells; after siRNA delivery, they are immediately cleared from the lungs ( Fig. 14 ). 132

The supramolecular organization of fullerene (C 60 ) is a unique approach for producing shape-controlled moieties on the nano-, micro-, and macro-scale. Nano-, micro-, and macro-scale supramolecular assemblies can be controlled via manipulating the preparation conditions to achieve unique optoelectronic properties. 133 The development of well-ordered and organized 1D, 2D, and 3D fullerene assemblies is essential for achieving advanced optical and organic-based electronic devices. 134 Fullerene-based nanostructured materials with new dimensions are being developed from zero-dimensional fullerene and tuned to achieve the desired characteristics. 1D C 60 fullerene nanowires have received substantial attention over other crystalline forms due to their excellent features of potential quantum confinement effects, low dimensionality, and large surface areas. 135

Carbon nanomaterials are also used as supports for catalysts, and the main reasons to use them are their high surface areas and electrical conductivities. Carbon supports strongly influence the properties of metal nanoparticles. In fuel cells, the carbon support strongly affects the stability, electronic conductivity, mass transport properties, and electroactive surface area of the supported catalyst. 136 In fuel cells, the degradation of some catalysts, such as platinum-based examples, and carbon is correlated and reinforced as a result of both being present. Carbon support oxidation is catalyzed by platinum and the oxidation of carbon accelerates platinum-catalyst release. Overall, this results in a loss of catalytically active surface area. 137 Fullerenes are considered suitable support materials due to their excellent electrochemical activities and stability during electrochemical reactions. 138 Due to their high stability and good conductivity, fullerenes can replace conventional carbon as catalyst support materials. Fullerenes are also used for the development of efficient solar cells. 139

Apart from the applications mentioned above, fullerenes have a broader spectrum of applications where they can be used to improve outcomes considerably. Fullerenes have the potential to be used in the development of superconductors. 140 The strong covalent bonds in fullerenes make them useful nanomaterials for improving the mechanical properties of composites. 141 The combination of fullerenes with polymers can result in good flame-retardant and thermal properties. 142 Fullerenes and their derivatives are used for the development of advanced lubricants. They are used as modifiers for greases and individual solid lubricants. 138 Fullerenes have tremendous medicinal importance due to their anticancer, antioxidant, anti-bacterial, and anti-viral activities. 104

Fullerenes are vital members of the carbon-based nanomaterial family and they certainly possess exceptional properties. This discussion further emphasizes their importance for advanced applications. However, the discovery of other carbon-based nanomaterials has put fullerenes in the shade, and the pace of their exploration has been reduced. As fullerenes are highly symmetrical molecules with unique properties, they can act as performance boosters, but more attention is needed from researchers for their practical expansion. 110

Single-walled carbon nanotubes consist of a seamless one-atom-thick graphitic layer, in which carbon atoms are connected through strong covalent bonds. 146 Double-walled carbon nanotubes consist of two single-walled carbon nanotubes. One carbon nanotube is nested in another nanotube to construct a double-walled carbon nanotube. 147 In multi-walled carbon nanotubes, multiple sheets of single-layer carbon atom are rolled up. In other words, many single-walled carbon nanotubes are nested within each other. From different types of nanotubes, it can be concluded that the nanotubes may consist of one, tens, or hundreds of concentric carbon shells, and these shells are separated from each other with a distance of ∼0.34 nm. 148 Carbon nanotubes can be synthesized via chemical vapor deposition, 149 laser ablation, 150 arc-discharge, 143 and gas-phase catalytic growth. 151

Single-walled carbon nanotubes display a diameter of 0.4 to 2 nm. The inner wall distance between double-walled carbon nanotubes was found to be in the range of 0.33 to 0.42 nm. MWCNT diameters are usually in the range of 2–100 nm, and the inner wall distance is about 0.34 nm. 147,152 However, it is essential to note that the diameters and lengths of carbon nanotubes are not well defined, and they depend on the synthesis route and many other factors. The electrical conductivities of SWCNTs and MWCNTs are about 10 2 –10 6 S cm −1 and 10 3 –10 5 S cm −1 , respectively. SWCNTs and MWCNTs also display excellent thermal conductivities of ∼6000 W m −1 K −1 and ∼2000 W m −1 K −1 , respectively. CNTs remain stable in air at temperatures higher than 600 °C. 153 These properties indicate that CNTs have obvious advantages over graphite.

Single-walled carbon nanotubes can display metallic or semiconducting behavior. Whether carbon nanotubes show metallic or semiconducting behavior depends on the diameter and helicity of the graphitic rings. 154 The rolling of graphene sheets leads to three different types of CNTs: chiral, armchair, and zigzag ( Fig. 15 ). 155

Carbon nanotubes demonstrate some amazing characteristics that make them valuable nanomaterials for possible practical applications. Theoretical and experimental studies of carbon nanotubes have revealed their extraordinary tensile properties. J. R. Xiao et al. used an analytical molecular structural mechanics model to predict SWCNT tensile strengths of 94.5 (zigzag nanotubes) and 126.2 (armchair nanotubes) GPa. 156 In another study, the Young's modulus and average tensile strength of millimeter-long multi-walled carbon nanotubes were analyzed and found to be 34.65 GPa and 0.85 GPa, respectively. 157 Carbon nanotubes possess a high aspect ratio. Due to their high tensile strength, carbon nanotubes are used to enhance the mechanical properties of composites.

Carbon nanotubes have become an important industrial material and hundreds of tonnes are produced for applications. 158 Their high tensile strength and high aspect ratio have made carbon nanotubes an ideal reinforcing agent. 159 Carbon nanotubes are lightweight in nature and are used to produce lightweight and biodegradable nanocomposite foams. 160 The structural parameters of carbon nanotubes define whether they will be semiconducting or metallic in nature. This property of carbon nanotubes is considered to be effective for their use as a central element in the design of electronic devices such as rectifying diodes, 161 single-electron transistors, 162 and field-effect transistors. 163 The chemical stability, nano-size, high electrical conductivity, and amazing structural perfection of carbon nanotubes make them suitable for electron field emitter applications. 164 The unique set of mechanical and electrochemical properties make CNTs a valuable smart candidate for use in lithium-ion batteries. 165 CNTs have the full potential to be used as a binderless free-standing electrode for active lithium-ion storage. CNT-based anodes can have reversible lithium-ion capacities exceeding 1000 mA h g −1 , and this is a substantial improvement compared with conventional graphite anodes. In short, the following factors play a role in controlling and optimizing the performances of CNT-based composites: 166 (i) the volume fraction of carbon nanotubes; (ii) the CNT orientation; (iii) the CNT matrix adhesion; (iv) the CNT aspect ratio; and (iv) the composite homogeneity.

For some applications, a proper stable aqueous dispersion of CNTs at a high concentration is pivotal to allow the system to perform its function efficiently and effectively. 167 One of the major issues associated with carbon nanotubes is their poor dispersion in aqueous media due to their hydrophobic nature. Clusters of CNTs are formed due to van der Waals attraction, π–π stacking, and hydrophobicity. The CNT clusters, due to their strong interactions, hinder solubility or dispersion in water or even organic-solvent-based systems. 168 This challenging dispersion associated with CNTs has limited their use for promising applications, such as in biomedical devices, drug delivery, cell biology, and drug delivery. 167 Carbon nanotube applications and inherent characteristics can be further tuned via suitable functionalization. The functionalization of carbon nanotubes helps scientists to manipulate the properties of carbon nanotubes and, without functionalization, some properties are not attainable. 169 The functionalization of nanotubes can be divided into two main categories: covalent functionalization and non-covalent functionalization.

The heating of CNTs under strongly acidic and oxidative conditions results in the formation of oxygen-containing functionalities. These functional groups, such as carboxylic acid, react further with other functional groups, such as amines or alcohols, to produce amide or ester linkages on the carbon nanotubes. 172 One of the main issues preventing the utilization of CNTs for biomedical applications is their toxicity. The cytotoxicity of pristine carbon nanotubes can be reduced via introducing carbonyl, –COOH, and –OH functional groups. Apart from functionalization through oxidized CNTs, the direct functionalization of CNTs is also possible. However, direct functionalization requires more reactive species to directly react with the CNTs, such as free radicals. Addition reactions to CNTs can cause a transformation from sp 2 hybridization to sp 3 hybridization at the point of addition. At the point where functionalization has taken place, the local bond geometry is changed from trigonal planar to tetrahedral geometry. Some addition reactions to the sidewalls of CNTs are shown in Fig. 16 . 155

It is important to discuss how the covalent functionalization of carbon nanotubes comes at the price of the degradation of the carbon sp 2 network. This substantially affects the electronic, thermal, and optoelectronic properties of the carbon nanotubes. 169 Efforts are being made to introduce a new method of covalent functionalization that can keep the π network of CNTs intact. Antonio Setaro et al. introduced a new [2+1] cycloaddition reaction for the non-destructive, covalent, gram-scale functionalization of single-walled carbon nanotubes. The reaction rebuilds the extended π-network, and the carbon nanotubes retained their outstanding quantum optoelectronic properties ( Fig. 17 ). 173

Polymers are frequently combined with CNTs to enhance their dispersion capabilities. Polymers interact with CNTs through CH–π and π–π interactions. 174 Hexanes and cycloalkanes are poor CNT solvents but the good solubility or dispersion of CNTs in these solvents is required for surface coating applications. Poly(dimethylsiloxane) (PDMS) macromer-grafted polymers have been prepared using PDMS macromers and pyrene-containing monomers that strongly adsorb on CNTs, thus improved the solubility of CNTs in chloroform and hexane. 176 The use of head–tail surfactants is another attractive way to achieve a fine dispersion of CNTs in an aqueous medium. In head–tail surfactants, the tail is hydrophobic and interacts with the CNT sidewalls, and the hydrophilic head groups interact with the aqueous environment to provide a fine dispersion. 177

For electrical applications, non-covalently functionalized CNTs are more preferred because the electrical properties of the CNTs are not compromised. CNTs have been non-covalently functionalized with a variety of biomolecules for the fabrication of electrochemical biosensors. 175 Non-covalently functionalized SWCNTs are used for energy applications. Single-walled carbon nanotubes (SWCNTs) have been non-covalently functionalized with 3d transition metal( II ) phthalocyanines, lowering the potential of the oxygen evolution reaction by approximately 120 mV compared with unmodified SWCNTs. 178 The toxicity of pristine CNTs toward living organisms can be lessened via using surfactant-functionalized CNTs. 170 However, in some cases, during polymer non-covalent functionalization, the polymer may wrap CNT bundles and make it difficult to separate the CNTs from each other. Polymers can develop into insulating wrapping that affects the CNT conductivity.

In the literature, several graphene-related materials have been reported, such as graphene oxide and reduced graphene oxide. 187 Among graphenoids, graphene oxide is a more reported and explored graphene-related material as a precursor for chemically modified graphene. The synthetic route to graphene oxide is straightforward, and it is synthesized from inexpensive graphite powder that is readily available. 188 Graphene oxide has many oxygen-containing functional groups, such as epoxy, hydroxyl, carboxyl, and carbonyl groups. The basal plane of graphene oxide is generally decorated with epoxide and hydroxyl groups, whereas the edges presumably contain carboxyl- and carbonyl-based functional groups. 189 The presence of active functional groups in graphene oxide allows its further functionalization with different polymers, small organic compounds, or other nanomaterials to realize several applications. 190

Graphene oxide, due to its oxygen functionality, is insulating in nature and displays poor electrochemical performance. The presence of oxygen functionalities in graphene oxide breaks the conjugated structure and localizes the π-electron network, resulting in poor carrier mobility and carrier concentration. 196 Its electrochemical performance is improved substantially after removing the oxygen-containing functional groups. 197 These functional groups can be removed or reduced via thermal, electrochemical, and chemical means. The product obtained after removing or reducing oxygen moieties is called reduced graphene oxide. The properties of reduced graphene oxide depend upon the effective removal of oxygen moieties from graphene oxide. The process used to remove oxygen-containing functionalities from graphene oxide will determine the extent to which reduced the properties of graphene oxide resemble pristine graphene. 198

Reduced graphene oxide is extensively used to improve the performances of various electrochemical devices. 199 It is essential to mention that even after reducing graphene oxide, some residual sp 3 carbon bonded to oxygen still exists, which somehow disturbs the movement of charge through the delocalized electronic cloud of the sp 2 carbon network. 200 Apart from this, the electrochemical activity of reduced graphene oxide is substantially high enough to manufacture electrochemical devices with improved performances. Recently, the demand for super-performance electrochemical devices has increased to overcome modern challenges relating to electronics and energy-storage devices. 201 Graphene-based materials are considered to be excellent electrode materials, and they can be proved to be revolutionary for use in energy-storage devices such as supercapacitors (SC) and batteries. Graphene-based electrodes improve the performances of existing batteries (lithium-ion batteries) and they are considered useful for developing next-generation batteries such as sodium-ion batteries, lithium–O 2 batteries, and lithium–sulfur batteries ( Fig. 18 ). Being flat in nature, each carbon atom of graphene is available, and ions can easily access the surface due to low diffusion resistance, which provides high electrochemical activity. 202

Graphene and its derivatives are extensively used for the development of electrochemical sensors. 203 The surfaces of bare electrodes are usually not able to sense analytes at trace levels and they cannot differentiate between analytes that have close electrooxidation properties due to their poor surface kinetics. The addition of graphene layers to the surfaces of electrodes can substantially improve the electrocatalytic activity and surface sensitivity towards analytes. 204 Graphene has definite advantages over other materials that are used as electrode materials for sensor applications. Graphene has a substantially high surface-to-volume ratio and atomic thickness, making it extremely sensitive to any changes in its local environment. This is an essential factor in developing advanced sensing tools, as all the carbon atoms are available to interact with target species.

Consequently, graphene exhibits higher sensitivity than its counterparts such as CNTs and silicon nanowires. 205 Graphene has two main advantages over CNTs for the development of electrochemical sensors. First, graphene is mostly produced from graphite, which is a cost-effective route, and second, graphene does not contain metallic impurities like CNTs can. Graphene offers many other advantages when developing sensors and biosensors, such as biocompatibility and π–π stacking interactions with biomolecules. 206 Graphene-based materials are ideal for the construction of nanostructured sensors and biosensors.

The mechanical properties of graphene are used to fabricate highly desired stretchable and flexible sensors. 207 Graphene can be utilized to develop transparent electrodes with excellent optical transmittance. It displays good piezoresistive sensitivity. Researchers are making efforts to replace conventional brittle indium tin oxide (ITO) electrodes with flexible graphene electrodes in optoelectronic devices such as liquid-crystal displays and organic light-emitting diodes. 208 For human–machine interfaces, transparent and flexible tactile sensors with high sensitivity have become essential. Graphene film (GF) and PET have been applied to develop transparent tactile sensors that exhibit outstanding cycling stability, fast response times, and excellent sensitivity ( Fig. 19 ). 209 Similarly, graphene is applied for the fabrication of pressure sensors. 210 Overall, graphene is an excellent material for developing transparent and flexible devices. 211,212

The use of graphene-based materials is an effective way to deal with a broad spectrum of pollutants. 213 There are many ways to deal with environmental pollution; among these, adsorption is an effective and cost-effective method. 214,215 Graphene-based adsorbents are found to be useful in the removal of organic, 216 inorganic, and gaseous contaminants. Graphene-based materials have some obvious advantages over CNT-based adsorbents. For example, graphene sheets offer two basal planes for contaminant adsorption, enhancing their effectiveness as an adsorbent. 192 GO contains several oxygen functional groups that impart hydrophilic features. Due to appropriate hydrophilicity, GO-based adsorbents can efficiently operate in water to remove contaminants. Moreover, graphene-oxide-based materials can be functionalized further through reactive moieties with various organic molecules to enhance their adsorption capacities. 217

In short, extensive research must continue in order to develop graphene-based materials with high performance and bring them to the market. Massive focus on graphene research is also justified due to the extraordinary features described in extensive theoretical and experimental research works.

Nanodiamonds possess a core–shell-like structure and display rich surface chemistry, and numerous functional groups are present on their surface. Several functional groups, such as amide, aldehyde, ketone, carboxylic acid, alkene, hydroperoxide, nitroso, carbonate ester, and alcohol groups, are present on nanodiamond surfaces, assisting in their further functionalization for desired applications ( Fig. 20 ). 226

Furthermore, nanodiamond surfaces can be homogenized with a single type of functional group according to the application requirements. 227 The use of nanodiamond particles as a reinforcing material in polymer composites has attracted great attention for improving the performance of polymer composite materials. The superior mechanical properties and rich surface chemistry of nanodiamonds have made them a superior material for tuning and reinforcing polymer composites. Nanodiamonds might operate via changing the interphase properties and forming a robust covalent interface with the matrix. 228 Nanodiamond (ND)-reinforced polymer composites have shown superior thermal stabilities, mechanical properties, and thermal conductivities. Nanodiamonds have shown great potential for energy storage applications. 229 Nanodiamonds and their composites are also used in sensor fabrication, environmental remediation, and wastewater treatment. 230,231 Their stable fluorescence and long fluorescence lifetimes have made nanodiamonds useful for imaging and cancer treatment. For biomedical applications, the rational engineering of nanodiamond particle surfaces has played a crucial role in the carrying of bioactive substances, target ligands, and nucleic acids, resisting their aggregation. 232,233 Nanodiamonds have a great future in nanotechnology due to their amazing surface chemistry and unique characteristics.

Carbon quantum dots can be synthesized through several chemical routes. 241–245 Some methodologies for synthesizing carbon dots are described in Fig. 21 . 246–248 Carbon itself is a black material and displays low solubility in water. In contrast, carbon quantum dots are attractive due to their excellent solubility in water. They contain a plethora of oxygen-containing functional groups on their surface, such as carboxylic acids. These functional moieties allow for further functionalization with biological, inorganic, polymeric, and organic species.

Carbon quantum dots are also called carbon nano-lights due to their strong luminescence. 248 In particular, carbon quantum dots offer enhanced chemiluminescence, 249,250 fluorescent emission, 251 two-photon luminescence under near-infrared pulsed-laser excitation, 252 and tunable excitation-dependent fluorescence. 253 The luminescence characteristics of carbon quantum dots have been used to develop highly sensitive and selective sensors. In most cases, a simple principle is involved in sensing with luminescent carbon quantum dots: their photoluminescence intensity changes upon the addition of an analyte. 254 Based on this principle, several efficient sensors have been developed using carbon quantum dots. 255–257 They can be used as sensitive and selective tools for sensing explosives such as TNT. Recognition molecules on the surfaces of carbon quantum dots can help to sense targeted analytes. Amino-group-functionalized carbon quantum dot fluorescence is quenched in the presence of TNT through a photo-induced electron-transfer effect between TNT and primary amino groups. This quenching phenomenon can help to sense the target analyte ( Fig. 22 ). 258 Chiral carbon quantum dots (cCQDs) can exhibit an enantioselective response. The PL responses of cCQDs were evaluated toward 17 amino acids and it was found that the PL intensity of the cCQDs was only substantially enhanced in the presence of L -Lys ( Fig. 22 ). 254

Carbon quantum dots have received significant interest in the fields of biological imaging and nanomedicine ( Fig. 23 ). 239 Direct images of RNA and DNA are essential for understanding cell anatomy. Due to the limitations of current imaging probes, tracking the dynamics of these biological macromolecules is not an easy job. Recently, membrane-penetrating carbon quantum dots have been developed for the imaging of nucleic acids in live organisms. 259 It is important to note that most of the carbon quantum dots utilized to attain cell imaging under UV excitation emit blue radiation. Some biological tissue also emits blue light, specifically that involving carbohydrates, and this interferes with cell imaging carried out with blue-emitting CQDs. This seriously hinders their potential in the field of biomedical imaging. Due to this reason, researchers are focusing on tuning CQDs in a way that their emission peak is red-shifted to avoid interference. 260 Carbon quantum dots with yellow and green fluorescence have been reported for bioimaging purposes. 261,262 The suitable doping of carbon quantum dots can red-shift the emission to enhance the bioimaging effectiveness. 263 Doped carbon quantum dots are capable of biological imaging and display advanced capabilities for scavenging reactive oxygen species. 264

Carbon quantum dots demonstrate photo-induced electron transfer properties 265 that make them valuable for photocatalytic, light-energy conversion, and other related applications. 266 Carbon quantum dots enhance the activities of other photocatalysts to which they are attached. Carbon quantum dots, along with photocatalysts, provide better charge separation and suppress the regeneration of photogenerated electron–hole pairs. Moreover, the proper implantation of carbon quantum dots into photocatalysts can broaden the photo-absorption region. Implanted carbon quantum dots form micro-regional heterostructures that facilitate photo-electron transport. 267 The implantation of carbon quantum dots into g-C 3 N 4 can substantially enhance charge transfer and separation efficiencies, prevent photoexcited carrier recombination, narrow the bandgap, and red shift the absorption edge. 268 The intrinsic catalytic activity of polymeric carbon nitride is improved as a result of the nano-frame heterojunctions formed with the help of CQDs. 269

Carbon quantum dots offer many advantages over conventional semiconductor-based QDs and, thus, they have attracted considerable researcher attention. 244 Due to their remarkable features, they have shown importance in recent years in the fields of light-emitting diodes, nanomedicine, solar cells, sensors, catalysis, and bioimaging. 236

The production of carbon nanohorns has some obvious advantages over carbon nanotubes, such as the ability for toxic-metal-catalyst-free synthesis and large-scale production at room temperature. Carbon nanotube synthesis involves metal particles, and harsh conditions, such as the use of strong acids, are required to remove metallic catalysts. This process introduces many defects into CNT structures and may cause a loss of carbon material. 270 Carbon nanohorns possess a wide diameter compared to CNTs. CNHs possess good absorption capabilities and their interiors are also available after partial oxidation, which provides direct access to their internal parts. Heat treatment under acidic or oxidative conditions facilitates the facile introduction of holes into carbon nanohorns. Holes in graphene sheets of single-walled carbon nanohorns can be produced with O 2 gas at high temperatures. A large quantity of material can be stored inside CNH tubes. 274 The surface area of CNHs is substantially enhanced upon opening the horns to make their interiors accessible. 275 Carbon nanohorns have great potential for energy storage, 275 electrochemiluminescence, 276 adsorption, 277 catalyst support, 278 electrochemical sensing, 279 and drug delivery system 273 uses. CNHs as catalyst supports can provide a homogeneous dispersion of Pt nanoparticles ( Fig. 25 ). The current density of Pt supported on single-walled carbon nanohorns is double compared to a fuel cell made from Pt supported on carbon black. 280 Thus, carbon nanohorns provide a better uniform dispersion that facilitates a high surface area and better catalyst performance.

5.2. Nanoporous materials

In nanoporous materials, the size distributions, volumes, and shapes of the pores directly affect the performances of porous materials for particular applications. It has become a hot area of research to develop materials with precisely controlled pores and arrangements. Recent research has focused more on the precise control of the shapes, sizes, and volumes of pores to produce nanoporous materials with high performance. Several state-of-the-art reviews are present in the literature that focus explicitly on the synthesis, properties, advances, and applications of nanoporous materials. 85,287–289 Based on the materials used, nanoporous materials can be divided into three main groups: inorganic nanoporous materials; carbonaceous nanoporous materials; and organic polymeric nanoporous materials.

Inorganic nanoporous materials include porous silicas, clays, porous metal oxides, and zeolites. The generation of pores in the material can introduce striking features into the material that are absent in non-porous materials. Nanoporous materials offer rich surface compositions with versatile characteristics. Nanoporous materials exhibit high surface-to-volume ratios. Their outstanding features and nanoporous framework structures have made these materials valuable in the fields of environmental remediation, adsorption, catalysis, sensing, energy conversion, purification, and medicine. 284,290

Porous silica is a crucial member of the inorganic nanoporous family. Over the decades, it has generated significant research interest for use in fuel cells, chemical engineering, ceramics, and biomedicine. It is essential to note that specific morphologies and pore size diameters are required for each application, and these can be achieved via tuning during the synthesis process. Nanoporous silica offers two functional surfaces: one is the cylindrical pore surfaces, and the second is the exterior surfaces of the nanoporous silica particles. The surfaces of nanoporous silica can be easily functionalized for the desired applications. The nanoporous silica surface is heavily covered with many silanol groups that act as reactive sites for functionalization ( Fig. 26 ). 291,292 For biomedical applications, mesoporous silica has emerged as a new generation of inorganic platform materials compared to other integrated nanostructured materials. Several factors make it a unique material for biomedical applications: 293,294 (a) its ordered porous structure; (b) its tunable particle size; (c) its large pore volume and surface area; (d) its biocompatibility; (e) its biodegradation, biodistribution, and excretion properties; and (f) its two functional surfaces. For instance, ordered MCM-48 nanoporous silica was used for the delivery of the poorly soluble drug indomethacin. It has been found that surface modification can control drug release. 295 Mesoporous silica-based materials have emerged as excellent materials for use in sustained drug delivery systems (SDDSs), immediate drug delivery systems (IDDSs), targeted drug delivery systems (TDDSs), and stimuli-responsive controlled drug delivery systems (CDDSs). The drug release rate from mesoporous silica can also be controlled via introducing appropriate polymers or functional groups, such as CN, SH, NH 2 , and Cl. Researchers are currently focusing on developing MSN-based (MSN = mesoporous silica nanoparticle) multifunctional drug delivery systems that can release antitumor drugs on demand in a targeted fashion via minimizing the premature release of the drug ( Fig. 27 ). 296

Hierarchically nanoporous zeolites are a vital member of the nanoporous material family. They are crystalline aluminosilicate minerals whose structures comprise uniform, regular arrays of nanopores with molecular dimensions. The microporous structures of zeolites contain pores that are usually below 1 nm in diameter. In zeolites, the micropores are uniform in shape and size, and these pores can effectively discriminate between molecules based on shape and size. 297 Currently, based on crystallography, more than 200 zeolites have been classified. 298 Zeolites have been proved to be useful materials in the field of host–guest chemistry. In solid catalysis, about 40% of the entire solid catalyst field is taken up by zeolites in chemical industry. The excellent catalysis success of zeolites is based on their framework stability, shape-selective porosity, solid acidity, and ion-exchange capacity. Oxygen tetrahedrally coordinates with the Al atoms in most zeolite crystalline silicate frameworks, resulting in charge mismatch between the oxide framework and Al. Extra-framework Na + ions compensate for this charge mismatch. The Na + ions are exchangeable for other cations such as H + and K + . 298 The zeolite crystalline networks are remarkable in that they provide high mechanical and hydrothermal stabilities. The most crucial task facing the zeolite community is to find new structures with desired functions and apply them more effectively for different applications.

Apart from these inorganic porous materials, several other metal- and metal-oxide-based nanoporous materials have been introduced that are more prominent for use in electrode material, catalyst, photodegradation, energy storage, and energy conversion applications. 299–302 Nanoporous metal-based materials are famous due to the nanosized crystalline walls, interconnected porous networks, and numerous surface metal sites that provide them with unique physical/chemical properties compared with their bulk counterparts and other nanostructured materials. 303 For example, nanoporous WO 3 films were developed via tuning the anodization conditions for photoelectrochemical water oxidation. It has been observed that the morphology of the film strongly affected the photoelectrochemical performance. 304 Nanoporous alumina is also a unique material in the inorganic nanoporous family due to several aspects. Nanoporous alumina can be prepared in a controlled fashion with any size and shape in polyprotic aqueous media via the anodic oxidation of the aluminum surface. The parallel arrangement of pores on alumina can easily be controlled from 5 nm to 300 nm, and alumina is stable in the range of 1000 °C. The anodizing time plays a significant role in controlling the pore length. Nanoporous alumina membranes offer various unique properties, such as pores of variable widths/lengths, temperature stability, and optical transparency. Nanoporous alumina pores can be filled with magnetically and optically active elements to produce the desired applications at the nanoscale level. Photoluminescent alumina membranes can be produced via introducing cadmium sulfide, gallium nitride, and siloxenes inside nanoporous alumina using appropriate precursors. 305 Porous alumina also acts as an efficient support and template for the designing of other nanomaterials. Palladium nanowires, 306 high aspect ratio cobalt nanowires, 307 and highly aligned Cu nanowires 308 were developed using porous alumina as a template. Ni–Pd as a catalyst was supported on porous alumina for hydrogenation and oxidation reactions. 309 Nanoporous anodic alumina is also considered to be an efficient material for the development of biosensors due to the ease of fabrication, tunable properties, optical/electrochemical properties, and excellent stability in aqueous environments. 310

Nanoporous carbon-based materials are a hot topic in the field of materials chemistry. Nanoporous carbon materials have become ubiquitous choices in the environmental, energy, catalysis, and sensing fields due to their unique morphologies, large pore volumes, controlled porous structures, mechanical, thermal, and chemical stabilities, and high specific surface areas ( Fig. 28A ). 311 Nanoporous materials are found to be useful in the treatment of water. The separation of spilled oil and organic pollutants from water has emerged as a significant challenge. 312–314 The design of materials that can allow the efficient separation of organic, dye, and metal contaminants from water has become a leading environmental research area. 315,316 Nanoporous carbon can be derived from different natural and synthetic sources. 317–319 Nanoporous carbon foam can be derived from natural sources, such as flour, pectin, and agar, via table-salt-assisted pyrolysis. The agar-derived nanoporous carbon foam showed high absorption capacities, a maximum of 202 times its own weight, for oil and organic solvents. Air filtration paper developed from carbon nanoporous materials and non-woven fabrics has shown a filtration efficiency of greater than 99% ( Fig. 28B ). 320 Nanoporous carbon can also be produced from other porous frameworks, such as metal–organic frameworks. MOF- and COF-based materials are promising precursors for nanoporous carbon-based materials. The direct carbonization of amino-functionalized aluminum terephthalate metal–organic frameworks has produced nitrogen-doped nanoporous carbon that shows an adequate removal capacity of 98.5% for methyl orange under the optimum conditions. 321 Fe 3 O 4 /nanoporous carbon was also produced with Fe salts as a magnetic precursor and MOF-5 as a carbon precursor for removing the organic dye methylene blue (MB) from aqueous solutions. 322 The mesoporous carbon removal efficiency could be further enhanced via modifying or functionalizing the surface with various materials. Unmodified mesoporous carbon has shown a mercury removal efficiency of 54.5%. This efficiency can be substantially improved to 81.6% and 94% upon modification with the anionic surfactant sodium dodecyl sulfate and cationic surfactant cetyltrimethyl ammonium bromide (CTAB), respectively. 323

Ordered nanoporous carbon, CNTs, and fullerenes are extensively applied for energy and environmental applications. The complicated synthesis routes required for fullerenes and CNTs have slowed down the full exploitation of their potential for highly demanding applications. In comparison, the synthesis of highly ordered nanoporous carbon is facile, and the properties of ordered nanoporous carbon are also appealing for energy and environmental applications. 311 CO 2 is a greenhouse gas, and its sustainable conversion into value-added products has become the subject of extensive research. A nitrogen-doped nanoporous-carbon/carbon-nanotube composite membrane is a high-performance gas-diffusion electrode applied for the electrocatalytic conversion of CO 2 into formate. A faradaic efficiency of 81% was found for the production of formate. 324 Nanoporous carbon materials modified with the non-precious elements P, S, N, and B have emerged as efficient electrode materials for use in the oxygen evolution reaction (OER), hydrogen evolution reaction (HER), oxygen reduction reaction (ORR), batteries, and fuel cells. 311,325–327

Nanoporous polymers, including nanoporous coordination polymers and crystalline nanoporous polymers, have emerged as impressive nanoporous materials. 328 Nanoporous polymers have many applications, and these materials are extensively being evaluated for gas separation and gas storage. The great interest in these applications arises from the presence of pores providing an exceptionally high Brunauer–Emmett–Teller (BET) surface area. Recently, new classes of metal organic framework and covalent organic framework porous materials have been reported that have shown exceptionally high and unprecedented surface areas. For instance, in 2010, a MOF was reported with a surface area of 6143 m 2 g −1 ; 329 in 2012, a MOF was reported with a surface area greater than 7000 m 2 g −1 ; 330 and in 2018, a MOF (DUT-60) was reported with a record surface area of 7836 m 2 g −1 . 331 Mesoporous DUT-60 has also shown a high free volume of 90.3% with a density of 0.187 g cm −3 . 331

Due to their exceptionally high surface areas and porous networks, these MOFs and COFs are ideal for gas storage. Air separation and post-combustion CO 2 capture have become integral parts of mainstream industries related to the energy sector in order to avoid substantial economic penalties. Due to the inefficiencies of available technology and the critical importance of this area, earnest efforts are being made to design gas-selective porous materials for the selective adsorption of desired gases. Nanoporous MOF- and COF-based materials can significantly capture CO 2 and help reach zero or minimum CO 2 emission levels. For instance, nanoporous fluorinated metal–organic frameworks have shown the selective adsorption of CO 2 over H 2 and CH 4 . 332 Hasmukh A. Patel et al. developed N 2 -phobic nanoporous covalent organic polymers for the selective adsorption of CO 2 over N 2 . The azo groups in the framework rejected N 2 , leading to CO 2 selectivity. 333 Nanoporous polymers that are superhydrophobic in nature can also be used for volatile organic compounds and organic contaminants. 334 Nanoporous polymers, due to the presence of a porous network, have been considered as highly suitable materials for catalyst supports. Furthermore, organocatalytic functional groups can be introduced pre-synthetically and post-synthetically into solid catalysts. 335

Nanoporous polymeric materials are amazingly heading towards being extremely lightweight with exceptionally high surface areas. These high surface areas and the fine-tuning of the nanopores has made these nanoporous materials, specifically MOFs and zeolites, ideal support materials for encapsulating ultrasmall metal nanoparticles inside void spaces to produce nanocatalysts with exceptionally high efficiencies. 336 In the coming years, more exponential growth of nanoporous materials is expected in the energy, targeted drug delivery, catalysis, and water treatment fields.

5.3. Ultrathin two-dimensional nanomaterials beyond graphene

However, from a material synthesis standpoint, a graphite-like layered form of Si does not exist in nature and there is no conventional exfoliation process that can generate 2D silicene, although single-walled 351 and multi-walled 352 silicon nanotubes and even monolayers of silicon have been synthesized via exfoliation methods. 353 Forming honeycomb Si nanostructures on substrates like Ag(001) and Ag(110) via molecular beam deposition, so-called “epitaxial growth”, was then proposed as a method for the architectural design of silicene sheets. 354–356 The successful synthesis of a silicene monolayer was first achieved on Ag(111) and ZrB 2 (0001) substrates in 2012; 357,358 later, various demonstrations were made using Ir(111), ZrB 2 (001), ZrC(111), and MoS 2 surfaces as the silicene growth substrates. 359–361 Despite various extensive studies to date involving the “epitaxial growth” of silicene on different substrates and investigations of the electronic properties, 357,362–364 the limited nanometer size, difficulties relating to substrate removal, and air stability issues have substantially impeded the practical applications of silicene. Bearing in mind all these known difficulties, Akinwande and co-workers recently reported a growth–transfer–fabrication process for novel silicene-based field-effect transistor development that involved silicene-encapsulated delamination with native electrodes. 365 An etch-back approach was used to define source/drain contacts in Ag film. Without causing any damage to the silicene, a novel potassium-iodide-based iodine-containing solution was used to etch Ag, avoiding rapid oxidation, unlike other commonly used Ag etchants. The results demonstrated that this was the first proof-of-concept study confirming the Dirac-like ambipolar charge transport predictions made about silicene devices. Comparative studies with a graphene system, the low residual carrier density, and the high gate modulation suggested the opening of a small bandgap in the experimental devices, proving that silicene can be considered a viable 2D nanomaterial beyond graphene.

Nonetheless, the synthesis of silicene on a large-scale is greatly limited, as “epitaxial growth” is the only promising method for obtaining high-quality silicene, and this presents an enduring challenge in relation to silicene research and development. Xu and co-workers recently introduced liquid oxidation and the exfoliation of CaSi 2 as a means for the first scalable preparation of high-quality silicene nanosheets. 366 This new synthetic strategy successfully induced the exfoliation of stacked silicene layers via the mild oxidation of the (Si 2 n ) 2 n layers in CaSi 2 into neutral Si 2 n layers without damage to the pristine silicene structure ( Fig. 29 ). The selective oxidation of pristine CaSi 2 into free-standing silicene sheets without any damage to the original Si framework was carried out via exfoliation in the presence of I 2 in acetonitrile solvent. Furthermore, the obtained silicene sheets yielded ultrathin monolayers or layers with few-layer thickness and exhibited excellent crystallinity. This 2D silicene nanosheet material was extensively explored as a novel anode, which was unlike previously developed silicon-based anodes for lithium-ion batteries. It displayed a theoretical capacity of 721 mA h g −1 at 0.1 A g −1 and superior cycling stability of 1800 cycles. Overall, during the last decade, silicene has been widely accepted as an ideal 2D material with many fascinating properties, suggesting great promise for a future beyond graphene.

Like other 2D materials, MXenes exhibit crystal geometry with a hexagonal close-packed structure based on the equivalent MAX-phase precursor, and the close-packed structure is formed from M atoms with X atoms occupying octahedral sites. 371 According to the formula, there are three representative structures of MXenes: M 2 XT x , M 3 X2T x , and M 4 X3T x . In these combinations, X atoms are formed with n layers, whereas M atoms have n + 1 layers ( Fig. 30 ). 372 Apart from graphene, MXenes are considered the most dynamic developing material, and they have incredible innovation potential amongst typical 2D nanomaterials because of their remarkable properties, such as hydrophilicity, conductivity, considerable adsorption abilities, and catalytic activity. These vital properties of MXenes suggest their use for various potential applications, including in the photocatalysis, electrocatalysis, 373,374 energy, 375 membrane-based separation, 376,377 and biological therapy 378 fields. In this section, we focus on describing new developments relating to MXenes that are utilized for electrocatalytic and energy storage applications, competing as alternatives to graphene materials.

Interestingly, due to the presence of abundant terminal groups, mainly –O, –OH, and –F, and their modifying nature, MXenes can exhibit outstanding hydrophilic properties and high conductivity and charge carrier mobility, making them a very attractive material for various electrocatalytic applications, such as the hydrogen evolution reaction, oxygen evolution reaction, oxygen reduction reaction, nitrogen reduction reaction, and CO 2 reduction reaction. To further increase their electrocatalytic activities, recent works involving MXenes have included incorporation with CNTs, 379 g-C 3 N 4 , 380 FeNi-LDH, 381 NiFeCo-LDH, 382 and metal–organic frameworks. 383

Cho and co-workers designed and developed MXene–TiO 2 2D nanosheets via the surface oxidation of MXene with defect-free control. These MXene–TiO 2 2D nanosheets were successfully implemented in nano-floating-gate transistor memory (NFGTM) providing a floating gate ( i.e. , multilayer MXene) and tunneling dielectric ( i.e. , the TiO 2 layer). A process of oxidation in water further represented a cost-effective and environmentally benign method, as depicted in Fig. 31 . The MXene NFGTM with an optimal oxidation process displayed exceptional nonvolatile memory features, having a great memory window, high programming/erasing current ratio, long term retention, and high durability. 384

There have been some exciting reports on 2D materials from the pnictogen family, particularly phosphorene. Recently, more attention has also been given to the remaining group 15 elements, 390 with the novel 2D materials arsenene, antimonene, and bismuthene being obtained from the key elements arsenic, antimony, and bismuth, respectively. It is reported that 2D monolayers of group 15 elements, including phosphorene allotropes, have five distinct honeycomb (α, β, γ, δ, and ε) and four distinct non-honeycomb (ζ, η, θ, and ι) structures, as depicted in Fig. 32 . Dissimilar crystal orientations were found for single-layered As, Sb, and Bi. Zeng and co-workers also reported comprehensive density functional theory (DFT) computations that proved the energetic stability and broad-range application of these materials in 2D semiconductors. 391 Previously, following theoretical predictions, Wu and co-workers successfully demonstrated that α-phosphorene showed lowest energy configurations in both honeycomb and non-honeycomb nanosheets. 392 In contrast, Zeng and co-workers proved that the buckled forms of 2D sheets of As, Sb, and Bi allotropes are the most stable structures, particularly their β phases. 391

Among monolayer group 15 family materials, 2D sheets of arsenic (As) and antimony (Sb) have gained considerable attention from researchers. 393,394 Studies have shown that As and Sb exhibit better stability than black phosphorus; they are highly stable at room temperature and less reactive to air, likely inhibiting the oxidization process. 395–398 Nevertheless, it has been demonstrated that the oxidation process is perhaps favorable for fine-tuning the electronic properties; increases in the indirect band gaps ranging from 0 to a maximum of 2.49 eV are found in free-standing arsenene and antimonene semiconductors. 399–403 Simultaneously, arsenene and antimonene can also be transformed into semiconductors with direct band gaps. These two 2D nanosheets can be used to design mechanical sensors, moving beyond common electronic and optoelectronic applications. These two extraordinary 2D nanosheets have been studied for their structural–property relationships via first-principles methods. 403–405

Continuing the characterization and structural property studies of arsenene carried out by Kamal 404 et al. and Zhang 403 et al. , Anurag Srivastava and co-workers analyzed applications of arsenene to explore the possibility of improving sensor devices that can be utilized to detect ammonia (NH 3 ) and nitrogen dioxide (NO 2 ) molecules. 406,407 They investigated the affinities of NH 3 and NO 2 molecules for pristine arsenene sheets, examining the binding energies, bonding distances, density distributions, and current–voltage features. The results showed that arsenene 2D sheets are highly durable, with significant electronic charge transfer. They also considered germanium-doped arsenene and characterized the 2D lattice based on molecular affinity relationships with respect to the dopant.

However, the incorporation of any dopants into 2D nanomaterials not only results in experimental difficulty but it also lowers the stability of 2D materials. 408 Recently, Dameng Liu and co-workers reported the electronic structures, focusing on band structures, band offsets, and intrinsic defect properties, of few-layer arsenic and antimony. 409 The spontaneous oxide passivation layer that is formed naturally on pristine antimonene provides excellent stability. 410 Very recently, Stefan Wolff and co-workers conducted DFT calculations on various single or few-layer antimony oxide structures to describe the stoichiometry and bonding type. Interestingly, the samples exhibited various structural stabilities and electronic properties with a wide range of direct and indirect band gaps. Showing band gaps between 2.0 and 4.9 eV, these 2D layers of antimonene exhibited the potential to be used as insulators or semiconductors. 411 The same group also analyzed Raman spectra and discussed identifying the predicted antimonene oxide structures experimentally. The enduring task of exploring the utility of antimonene has boosted recent research interest in 2D nanomaterials due to the broad range of potential applications, such as their use in electrochemical sensors, 412,413 stable organic solar cells, 414 and supercapacitors 415 to name a few.

The 2D MOF nanosheets are also evaluated for the development of high-performance power-storage devices. For example, Li et al. 427 recently reported two novel Mn-2D MOFs and Ni-2D MOFs as anode materials for rechargeable lithium batteries. The Mn-based ultrathin metal–organic-framework nanosheets, due to thinner nanosheets, a higher specific surface area, and smaller metal ion radius, had structural advantages over Ni-based ultrathin metal–organic-framework nanosheets. Due to these features, the Mn-based ultrathin metal–organic-framework nanosheets displayed a high reversible capacity of 1187 mA h g −1 at 100 mA g −1 for 100 cycles and a rate capability of 701 mA h g −1 even at 2 A g −1 .

The expensive metal oxides utilized in the catalytic process can be replaced in due course by 2D-MOF-based nanosheets with exposed metal sites that impart an adjustable pore structure, ultrathin thickness, a high surface-to-volume atom ratio, and high design flexibility. As a result, 2D-MOFs have extensively been explored for various electrocatalytic applications, including the hydrogen evolution reaction (HER), oxygen evolution reaction (OER), oxygen reduction reaction (ORR), and carbon dioxide reduction reaction (CO 2 RR). For example, Marinescu et al. 428 combined cobalt dithiolene species with benzenehexathiol (BHT) and yielded 2D-MOFs capable of acting as electrocatalysts for the HER in water ( Fig. 34 ). In the presence of 2D-MOF sheets, a high current density of 41 mA cm −2 , at −0.8 V vs. SHE and a pH value of 1.3, is observed. Similarly, Feng et al. 429 also developed single-layer Ni-based 2D-MOF sheets that are highly effective for electrocatalytic hydrogen evolution. Later, Patra et al. 430 reported similar 2D sheets from covalent organic frameworks (2D-COFs) as metal-free catalysts for HER applications. 2D-MOFs are also being explored as active catalysts for the OER process. For example, Xu et al. 431 reported the preparation of 2D Co-MOF sheets using polyvinylpyrrolidone as a surfactant under mild solvothermal conditions. These novel 2D Co-MOFs displayed ultrathin nanosheets with many surface-based metal active sites, improving the overall OER performance.

Interestingly, experimental electrochemical measurement data showed that Co-MOF sheets offer a low overpotential ( i.e. , 263 mV at 10 mA cm −2 ). Similarly, Wang et al. 432 also reported that double-metal 2D-sheets (2D NiFe MOFs) consisting of a very ultrathin structure with a thickness of ∼10 nm further offer a low overpotential of 260 mV at 10 mA cm −2 . In other reports, Zhang et al. 433 successfully performed the OER process with ultrathin 2D-MOF sheets prepared via electrochemical and chemical exfoliation strategies.

Recent work on the catalytic activity of 2D-MOFs has also been reported in relation to the ORR and CO 2 RR because of their layered crystal structures and high-volume modifiable porous structures. For example, Dincă et al. 434 demonstrated that ultrathin layered conductive sheets of the 2D-MOF Ni 3 (HITP) 2 (HITP = 2,3,6,7,10,11-hexaiminotriphenylene) could actively be utilized as a catalyst in an alkaline medium for the ORR process. These 2D-MOF sheets show high stability while retaining 88% of the initial current density over 8 h at 0.77 V vs. RHE. In another report, through fabricating Co x Zn 2− x (bim) 4 2D-sheets as precursors, Zhao et al. 435 successfully synthesized cobalt nanodots (Co-NDs) with bimetallic Co x Zn 2− x (bim) 4 nanosheets encapsulating few-layer graphene (Co@FLG). For the CO 2 RR, a cobalt–porphyrin-containing 2D-MOF was achieved for the selective electrochemical reduction of CO 2 to CO with enhanced stability by Peidong Yang and co-workers. 436 The results further proved that these thin-film catalysts have the highest selectivity for CO ( i.e. , 76%) at −0.7 V vs. RHE with the little-to-no substantial decrease in activity over 7 h at −0.7 V vs. RHE, and 16 mL of CO was produced. Besides, like many other porous materials, 2D-MOFs were also shown to be a supporting platform for catalytic nanoparticles because of their high specific surface areas and favorable porosity distributions. To this end, an example can be noted from Wang et al. 437 reporting that fine porous MOF-5 nanosheets can be utilized to immobilize Pd nanoparticles.

5.4. Metal-based nanostructured materials

As discussed, catalysis is one of the main uses of metal-based nanostructured materials. A continuous increase in the demand for energy, the rapid depletion of conventional energy reservoirs, and rising concerns over the emission of CO 2 have increased the challenges and urgency in the energy field. 460 Metal-based nanostructured materials are extensively being explored to produce alternative clean and renewable energy sources. A range of metal-based nanomaterials has been evaluated and is under consideration for developing robust electrodes that can be effectively applied to water splitting, batteries, and solar cells.

High energy demands have led to more pressure to improve the performances of existing highly demanded lithium-ion batteries. Researchers have focused on improving their lifetimes, sizes, and safety. 462 Nanostructured metal-oxide-based materials are promising electrode materials for use in high-performance charge-storage devices. A metal-based nanostructured electrode is evaluated as both the anode and cathode to overcome the challenges of conventional electrodes. 463 In a conventional LIB, LiCoO 2 was used as the cathode material. Controlled morphology plays a crucial role in determining the performance of a material. Powder composed of spherical particles of LiNi 0.8 Co 0.2 O 2 showed a higher tap density compared to irregular particles and the material substantially improved the power density of secondary lithium batteries. 464 Hierarchical nanostructures of metal-based oxides (such as 3D hierarchical ZnCo 2 O 4 nanostructures) have emerged as a new trend for the development of high-capacity electrodes for lithium-ion batteries. 465 Since their commercialization by Sony in the early 1990s, LIBs have achieved tremendous success in bringing portable electronic devices to the market. However, their sustainable development on the grid-scale is hampered due to limited Li resources in nature, and this is causing a continuous increase in cost. 466 Sodium-ion batteries are in the spotlight to replace powerful lithium-ion batteries due to the widespread availability of sodium and its lower cost compared with lithium. 467 It is essential to note that, in terms of energy densities for SIBs, it is difficult to bypass LIBs because of the low standard electrochemical potential and higher weight of Na. SIBs could be proved to be ideal for those applications where cost is a critical factor compared to energy density. 466

SIBs also operate similarly to LIBs, based on an intercalation mechanism. SIBs also consist of cathode and anode electrodes separated through an electrolyte. During the charging process, sodium ions are extracted from the cathode and inserted into the anode via the electrolyte. In the discharging process, the electrons leave the anode through an external circuit to reach the cathode, providing electricity to the load, whereas Na + moves to the cathode during this process. The radius of Na + (1.02 Å) is greater than that of Li + (0.76 Å), making it challenging to intercalate into electrode materials. 468 Thus, appropriate electrode materials are required in which fast Na-ion insertion and extraction is possible. However, SIBs are suffering from a lack of appropriate electrode materials. It is important to develop electrode materials that have enough interstitial space within their crystallographic structures and better electrochemical performance. Among the various proposed electrode materials, Na x MO 2 layered transition-metal oxides (M = V, Fe, Cu, Co, Ni, Cr, Mn, and their combinations) are considered to be promising electrode materials for SIBs. Layered metal oxides are considered to be promising electrode materials due to their facile scalable synthesis, simple structures, appropriate operating potentials, and high capacities. 469,470 Large volume expansion and poor kinetics during the charge–discharge process can severely affect the cyclability and performance of SIBs. One of the effective strategies to deal with the mechanical stress triggered by large volume changes is the design of hollow or porous structures. In response, three-dimensional network-based Sb 2 O 3 @Sb composite anode materials can help to relieve the volume-change-related stress through their uniform porous networks and provide better transportation channels for Na + . 471

The large volume expansion of electrodes can also be buffered via designing 2D metal-oxide materials with large interlayer spacing. The ultrathin nanosheets provide high reversible capacity with enhanced cycling stability and contribute to providing reaction sites for electrons/ions, decreasing the diffusion distance, providing effective diffusion channels, and facilitating fast charge/discharge for sodium and lithium. 2D SnO nanosheet anodes were evaluated for SIBs. The capacity and cyclic stability improved, as the number of atomic SnO layers is decreased in the sheets. 472 Sb is a promising anode material, but during the sodiation/desodiation processes, huge volume expansion of 390% is observed, which hinders its practical use. Nanostructured Sb in the form of nanorod arrays with large interval spacing displays the great capacity to accommodate volume changes during cycling. 473 A comparison of various nanostructured metal-based electrodes for various charge storage purposes is shown in Table 3 . Overall, well-structured metal or metal-based oxide nanomaterials have the capacity to resolve current issues relating to charge storage devices.

Recently, an immense focus of research has been to produce H 2 fuel via water-splitting to replace conventional fossil fuels. This will help to eliminate emissions from the use of carbonaceous species. 484 Electrochemical method are considered simple water splitting approaches, as these methods only require an applied voltage and water as inputs to produce hydrogen fuel. 485 The coupling of solar irradiation to electrochemical water splitting has enhanced the performance and reduced the process cost. Due to these reasons, this has become a hot area of research. 486 During water electrolysis, H 2 is produced through the hydrogen evolution reaction at the cathode and O 2 is produced through the oxygen evolution reaction at the anode. However, water splitting is not so straightforward, and it requires an efficient catalyst that can facilitate the splitting of water. Metal- and metal-oxide-based catalysts are extensively being explored for water splitting. For the HER reaction, Pt-based catalysts are found to be suitable, whereas for OER reactions, Ir-/Ru-based compounds are found to be benchmark catalysts. Scarcity and high cost have limited the widespread use of these metals. The barrier of noble-metal cost can be mitigated through developing noble-metal nanostructured surfaces that produce more active sites or via depositing monolayers of noble metals on low-cost materials. The alloying of noble metals with other metals has enhanced site-specific activity. 484 At present, more focus is being placed on developing noble-metal-free catalysts for water splitting. 485 Usually, an efficient electrocatalyst is characterized by: 487 a low overpotential; high stability; low production costs; and high electrocatalytic activity.

The nano-structuring of catalysts is an effective tool to boost their surface areas. The electrolysis of water occurs at the surface of a catalyst, and nanostructured catalysts provide more active sites and the better diffusion of ions and electrolytes. 484 Non-noble metals that are under observation for the development of HER electrocatalysts include nickel (Ni), tungsten (W), iron (Fe), molybdenum (Mo), cobalt (Co), and copper (Cu). 487 For instance, a noble metal-free catalyst, carbon-decorated Co 3 O 4 nanoarrays on carbon paper, required a small overpotential of 370 mV to reach a current density of 10 mA cm −2 . It can maintain a current density of 100 mA cm −2 for 413.8 h and 86.8 h under alkaline and acidic conditions, respectively. 488

Metal-based semiconductor materials play a crucial role in a range of applications. For photoelectrochemical water splitting, the semiconductor material plays a central role in the solar-to-hydrogen conversion efficiency. Some critical features are prerequisites when it comes to selecting the right semiconductor material for the photoelectrochemical splitting of water: 489 an extraordinary capacity to absorb visible light; an appropriate bandgap; suitable valence and conduction band positions; commercial feasibility; and chemical stability.

For an ideal semiconductor for water splitting, the valence band and conduction band edge positions must straddle the oxidation and the reduction potentials of water. Metal oxides have received significant attention among semiconductors due to their wide band gap distributions, remarkable photo-electrochemical stabilities, and favorable band edge positions. 490 Semiconductor-based photoelectrodes become excited upon light irradiation, and electrons from the valence band move to the unoccupied conduction band. Some of the generated electrons at the cathode surface reduce protons to hydrogen gas, whereas holes at the photoanode produce oxygen gas via water splitting. 490 As a result, various nanostructured metal oxides can be used as photoelectrode materials, such as WO 3 , 491 Cu 2 O, 492 TiO 2 , 493 ZnO, 494 SnO 2 , 495 BiVO 4 , 496 and α-Fe 2 O 3 , 490 for the efficient splitting of water. As discussed, the nano-structuring of semiconductors can significantly impact the electrode photoelectrochemical performance during water splitting.

Metal-based nanomaterials have been used for the development of sensitive sensors. These metal-based sensors can replace the complex and expensive instruments that are conventionally used for the sensing of analytes. Metal-oxide-based sensors have the interesting characteristics of low detection limits, low cost, high sensitivity, and facile operation. 497 Mostly, semiconducting metal-oxide-based sensors are used for the sensing of toxic, flammable, and exhaust gases. Semiconductor metal oxides with a size in the range of 1–100 nm have been significantly investigated as gas sensors due to their size-dependent properties. The geometry and size of a nanomaterial can considerably affect the hole and electron movement in semiconductors. 498 The surface-to-volume ratio and surface area are substantially enhanced at the nanoscale level, and this is amazingly beneficial for sensing. Chemiresistive semiconducting metal oxides are potential candidates for gas sensing due to the following features: 499 rapid response times; fast recovery times; low cost; simple electronic interfaces; user-friendliness and low maintenance; and abilities to sense a wide range of gases.

Electrode materials decorated with metal- or metal-oxide-based nanostructured materials have shown better responses and selectivity for determining various analytes over conventional electrode materials. The nano-sized metal structures act as an electrocatalyst and electronic wires to provide rapid electron transfer between the transducers and analyte molecules. 500 The electrochemical redox reaction of H 2 O 2 can be improved via the thermally controlled anchoring of Pt NPs on the electrode surface. 501

Currently, researchers are not just concentrating on the development of randomly shaped nanomaterials; instead, they are very focused on and interested in the rational design of materials with controlled nano-architectures for boosting their performances for specific applications. As a result, extensive research has been carried out to develop metal-based materials with controlled dimensions to achieve better catalytic responses. Particle morphology is a crucial factor in the performance of nanomaterials for specific applications. Laifa Shen et al. rationally designed an electrode architecture via growing mesoporous NiCo 2 O 4 nanowire arrays on carbon textiles, which boosted the electrode performance ( Fig. 37 ). 474

The same materials with different morphologies can produce different outcomes. For instance, MnO 2 nanoflowers have provided high initial sodium-ion storage capacity compared with MnO 2 nanorods. 481 Radha Narayanan and Mostafa A. El-Sayed have analyzed various nanoscale morphologies of Pt, such as tetrahedral, cubic, and near-spherical nanoparticles. The highest rate constant is observed with tetrahedral nanoparticles and the lowest rate constant was observed with cubic nanoparticles, whereas spherical nanoparticles exhibited an intermediate rate constant during catalysis. 502 Xiaowei Xie et al. found that Co 3 O 4 nanorods show high activity compared to conventional Co 3 O 4 nanoparticles for the low-temperature oxidation of CO. 503 The catalytic activity of metal-based nanomaterials is strongly affected by their shape. 504 Shape-defined mesoporous materials (TiO 2 ) have shown superior photoanode activities ( Fig. 38 ). 505 As a result, in the literature, several nanostructured morphologies of metal-based materials, such as nanotubes, 506,507 nanorods, 508,509 nanoflowers, 510 nanosheets, 511 nanowires, 512 nanocubes, 513 nanospheres, 514,515 nanocages, 516 and nanoboxes, 517 have been reported for a range of applications.

Hollow nanostructures have surfaced as an amazing class of nanostructured material, and they have received significant attention from researchers. Hollow nanostructures have the unique features of: 518,519 low density; abundant inner void spaces; large surface areas; and the ability to act as nanoscale containers with high loading capacity, nanoreactors, and nanocarriers.

Various metal-based hollow nanostructures, such as hollow SnO 2 , 520 hollow palladium nanocrystals, 521 Co–Mn mixed oxide double-shell hollow spheres, 521 hollow Cu 2 O nanocages, 522 three-dimensional hollow SnO 2 @TiO 2 spheres, 523 hollow ZnO/Co 3 O 4 nano-heterostructure, 524 triple-shell hollow α-Fe 2 O 3 , 525 and hierarchical hollow Mn-doped Ni(OH) 2 nanostructures, 526 have been developed for various applications. The presence of nanoscale hollow interiors and functional shells imparts them with great potential for gas sensing, catalysis, biomedicine, energy storage, and conversion. 519

From this discussion, it can be concluded that metal-based nanostructured materials have great potential compared to their bulk counterparts. The conversion of materials to the nanoscale is not enough to achieve high performance with better selectivity. Now, research is switching from conventional nanomaterials to more advanced and smartly designed nanomaterials. In modern research, nanomaterials are being designed with better-controlled morphologies and regulated features.

5.5. Core–shell nanoparticles

A spherical nanoparticle core–shell nanostructure is a practical way to introduce multiple functionalities on the nanoscopic length scale. 528 The properties arising from the core or shell can be different, and these properties can be tuned via controlling the ratio of the constituent materials. The shape, size, and composition play a critical role in tuning the core–shell nanoparticle properties. 529 The shell material can help to improve the chemical and thermal stabilities of the core material. The core–shell design has become effective where an inexpensive material cannot be used directly due to its instability or easily oxidizable nature. The core can consist of an easily oxidizable inexpensive metal, whereas the shell might consist of noble metals, oxides, polymers, or silica. 530 For instance, magnetic nanoparticles when prepared can be sensitive toward air, acids, and bases. Magnetic nanoparticles can be protected via coating with organic or inorganic shells. 528

Core–shell metal nanoparticles are an emerging nanostructured material with great potential in the fields of energy and catalysis. 531 The first report of core–shell nanoparticles (2007) for supercapacitor applications consisted of a polyaniline/multi-walled-carbon-nanotube composite (PANI/MWNTs). 532 Metal-based core–shell structured nanoparticles have shown enhanced catalytic performance due to their shape-controlled properties. 533 Ming-Yu Kuo et al. developed Au@Cu 2 O core–shell particles with controllable shell thicknesses that acted as a dual-functional catalyst. The shell thickness of Cu 2 O increased with an increasing concentration of Cu 2+ precursor. The thicknesses of the shells of Au@Cu 2 O-1.5 (12.2 ± 1.7 nm), Au@Cu 2 O-2 (13.2 ± 1.8 nm), Au@Cu 2 O-3 (18.2 ± 2.2 nm), and Au@Cu 2 O-4 (20.8 ± 2.5 nm) due to various concentrations are shown in Fig. 40 . 534 A NiO@SiO 2 core–shell catalyst provided a higher yield of acrylic acid from acetylene hydroxycarbonylation. 535 Core–shell architecture can be used to prevent active metal nanoparticles from oxidation during operation. For instance, a plasmonic photocatalyst was developed that consisted of silver nanoparticles embedded in titanium dioxide. The direct contact of Ag with TiO 2 could lead to its oxidization; this is prevented via developing core–shell architecture in which Ag is used as the core and SiO 2 is used as a shell to protect it. 536 Another excellent option is to replace an expensive core with a non-noble metal to reduce the core–shell cost while using a thin layer of a noble metal that consumes a small amount of metal as the shell. This will ensure the prolonged stability of the catalyst during operation. 533 Overall, core–shell morphologies provide better catalytic activity due to the synergistic effect of the metallic core–shell components. 152

Among the several classes of nanomaterials, core–shell nanoparticles are found to be more promising for different biomedical applications. For instance, magnetic nanoparticles are considered to be useful for biomedical applications due to the following reasons: (a) aggregation is prevented due to superparamagnetism; (b) delivery and separation can be controlled using an external magnetic field; (c) they can be appropriately dispersed; and (d) there is the possibility of functionalization. A range of magnetic nanoparticles is available, such as NiO, Ni, Co, and Mn 3 O 4 . The most famous example is iron oxide, but uncoated iron oxides are unstable under physiological conditions. This may result in controlled drug delivery failure due to improper ligand surface binding and the promotion of the formation of harmful free radicals. Therefore, the formation of shells around magnetic nanoparticles has tremendous significance for biomedical applications. 537 One of the approaches is to use gold shells on magnetic nanoparticles. Au NPs are also called surface plasmons and they substantially enhanced the absorption of light in the visible and near-infrared regions. Thus, coating magnetic nanoparticles with a Au shell can result in a core–shell nanostructure that displays both optical and magnetic functionality in combination. 529

Numerous biocompatible core–shell nanoparticles are being developed for photothermal therapy, as core–shell materials are found to be useful for photothermal therapy. Hui Wang et al. have developed bifunctional core–shell nanoparticles for dual-modal imaging-guided photothermal therapy. The core–shell nanoparticles consist of a magnetic ∼9.1 nm core of Fe 3 O 4 covered by an approximately 3.4 nm fluorescent carbon shell. The Fe 3 O 4 core leads to superparamagnetic behavior, whereas the carbon shell provides near-infrared (NIR) fluorescence properties. The bifunctional nanoparticles have shown dual-modal imaging capacity both in vivo and in vitro . The iron oxide–carbon core–shell nanoparticles absorbed and converted near-infrared light to heat, facilitating photothermal therapy. 538 Au-Based core–shell structures are also being prepared for photothermal therapy. Bulk gold is biocompatible, but Au NPs can accumulate in the spleen and liver, causing severe toxicity. Koo Chul Kwon et al. have developed Au-NP-based core–shell structures that did not result in any gross or histological lesions in the major organs of mice, which revealed that this is a potent and safe agent for photothermal cancer therapy. The core–shell nanoparticles consisted of proteinticle/gold (PGCS-NP) and were developed via proteinticle surface engineering. PGCS-NP was injected intravenously into mice with tumors, and the injected core–shell nanoparticles successfully reached the EGFR-expressing tumor cells. The tumor size was significantly reduced upon exposure to near-infrared laser irradiation ( Fig. 41 ). No accumulation of Au NPs was observed in the mice organs, which indicated that PGCS-NP disassembled into many tiny gold dots, which were easily excreted by the kidneys and liver without causing any toxicity. 539 In another example, multifunctional Au@graphene oxide nanocolloid core@shell nanoparticles were developed, in which the core and shell consisted of gold and a graphene oxide nanocolloid, respectively. The developed core–shell structure showed multifunctional properties, allowing Raman bioimaging and photothermal/photodynamic therapy with low toxicity. 540 Apart from this, numerous other core–shell nanoparticles, such as polydopamine–mesoporous silica core–shell nanoparticles, 541 AuPd@PVP core–shell nanoparticles, 542 Au@Cu 2− x S core–shell nanoparticles, 543 bismuth sulfide@mesoporous silica core–shell nanoparticles, 544 and Ag@S-nitrosothiol core–shell nanoparticles, have been used for photothermal therapy. 545

Due to their unique features and the combination of properties from the shell and core, these core–shell nanoparticles have received considerable interest in many fields, ranging from materials chemistry to the biomedical field. For electrochemical reactions, the core–shell structure conductivity can be enhanced via conducting polymers, carbon materials, and metals. Core–shell nanoparticles as electrode materials showed better performance compared to single components. Most of the core materials are prepared via hydrothermal methods, and shells can be prepared via hydrothermal or electrodeposition methods. 546 Even though significant progress has been made relating to the synthesis methods of core–shell materials, a major challenge is the high-quality production of core–shell materials in more effective ways for required applications, specifically biomedical applications.

6. Challenges and future perspectives

(a) The presence of defects in nanomaterials can affect their performance and their inherent characteristics can be compromised. For instance, carbon nanotubes are one of the strongest materials that are known. However, impurities, discontinuous tube lengths, defects, and random orientations can substantially impair the tensile strength of carbon nanotubes. 547

(b) The synthesis of nanomaterials through cost-effective routes is another major challenge. High-quality nanomaterials are generally produced using sophisticated instrumentation and harsh conditions, limiting their large-scale production. This issue is more critical for the synthesis of 2D nanomaterials. Most of the methods that have been adopted for large-scale production are low cost, and these methods generally produce materials with defects that are of poor quality. The controlled synthesis of nanomaterials is still a challenging job. For example, a crucial challenge associated with carbon nanotube synthesis is to achieve chiral selectivity, conductivity, and precisely controlled diameters. 548,549 Obtaining structurally pure nanomaterials is the only way to achieve the theoretically calculated characteristics described in the literature. More focused efforts are required to develop new synthesis methods that overcome the challenges associated with conventional methods.

(c) The agglomeration of particles at the nanoscale level is an inherent issue that substantially damages performance in relevant fields. Most nanomaterials start to agglomerate when they encounter each other. The process of agglomeration may be due to physical entanglement, electrostatic interactions, or high surface energy. 550 CNTs undergo van der Waals interactions and form bundles, making it difficult to align or properly disperse them in polymer matrices. 159 Similarly, graphene agglomeration is triggered by the basal planes of graphene sheets due to π–π interactions and van der Waals forces. Due to severe agglomeration, the high surface areas and other unique graphene features are compromised. These challenges hinder the practical application of high-throughput electrode materials or composite materials for various applications. 551

(d) The efficiency of nanomaterials can be tuned via developing 3D architectures. 3D architectures have been tried with several nanomaterials, such as graphene, to improve their inherent features. 3D architectures of 2D graphene have provided high specific surface areas and fast mass and electron transport kinetics. This has become possible due to the combination of the exceptional intrinsic properties of graphene and 3D porous structures. 194,552 The combination of graphene and CNT assemblies into 3-D architectures has emerged as the most investigated nanotechnology research area. Porous architectures of other nanomaterials can be developed to enhance their catalysis performance through providing nanomaterial interior availability.

(e) 2D ultrathin materials are an outstanding class of nanomaterial with promising theoretical properties; however, very little experimental evaluation of these materials has been done, apart from the case of graphene. The synthesis and stability of 2D ultrathin materials are some of the major challenges associated with them. In the future, more focus is anticipated to be placed on their synthesis and practical utilization.

(f) Nanomaterial utilization in industry is being increased, and there is also demand for nanoscale material production at higher rates. Moreover, nanotechnology research has vast horizons; the exploration of new nanomaterials with fascinating features will continue and, in the future, more areas will be discovered. One of the significant concerns relating to nanomaterials that cannot be overlooked is their toxicity, which is still poorly understood, and this is a serious concern relating to their environmental, domestic, and industrial use. The extent to which nanoparticle-based materials can contribute to cellular toxicity is unclear. 553 There is a need for the scientific community to put efforts into reducing the knowledge gap between the rapid development of nanomaterials and their possible in vivo toxicity. A proper and systematic understanding of the interaction of nanomaterials with cells, tissues, and proteins is critical for the safe design and commercialization of nanotechnology. 14

The future of advanced technology is linked with advancements in the field of nanotechnology. The dream of clean energy production is becoming possible with the advancement of nanomaterial-based engineering strategies. These materials have shown promising results, leading to new generations of hydrogen fuel cells and solar cells, acting as efficient catalysts for water splitting, and showing excellent capacity for hydrogen storage. Nanomaterials have a great future in the field of nanomedicine. Nanocarriers can be used for the delivery of therapeutic molecules.

7. Conclusions

Conflicts of interest, acknowledgements.

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Synthesis, characteristics and medical applications of plant nanomaterials

• Published: 20 November 2020
• Volume 252 , article number  108 , ( 2020 )

Cite this article

• Lidong Du 1   na1 ,
• Ruoyu Zhang 2   na1 ,
• Hanchao Yang 4 ,
• Shaojian Tang 3 ,
• Zhaohua Hou 5 ,
• Jinjin Jing 2 ,
• Bingjie Lin 2 ,
• Shujie Zhang 2 ,
• Zhong Lu 1 , 4 &
• Peng Xue   ORCID: orcid.org/0000-0002-5537-1648 2  

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Main conclusion

The recent preparations of metal nanoparticles using plant extracts as reducing agents are summarized here. The synthesis and characterization of plant–metal nanomaterials and the progress in antibacterial and anti-inflammatory medical applications are detailed, providing a new vision for plant-based medical applications.

The medical application of plant-metal nanoparticles is becoming a research hotspot. Compared with traditional preparation methods, the synthesis of plant-metal nanoparticles is less toxic and more eco-friendly, increasing application potential. Highly efficient plant-metal nanoparticles are usually smaller than 100 nm. This review describes the synthesis, characterization and bioactivities of gold- and silver-plant nanoparticles as examples and clearly explained their antibacterial and anticancer mechanisms. An analysis of actual cases shows that the synthetic method and type of plant extract affect the activities of the products.

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Lidong Du and Ruoyu Zhang authors have contributed equally to this work.

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School of Clinical Medical, Weifang Medical University, Weifang, 261053, People’s Republic of China

Lidong Du & Zhong Lu

School of Public Health, Weifang Medical University, Weifang, 261053, People’s Republic of China

Ruoyu Zhang, Jinjin Jing, Bingjie Lin, Shujie Zhang & Peng Xue

School of Pharmacy, Weifang Medical University, Weifang, 261053, People’s Republic of China

Shaojian Tang

Affiliated Hospital of Weifang Medical University, Weifang, 261053, People’s Republic of China

Hanchao Yang & Zhong Lu

College of Food Science and Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, People’s Republic of China

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• Review Article
• Published: 17 August 2020

Advances in nanomaterial vaccine strategies to address infectious diseases impacting global health

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Despite the overwhelming success of vaccines in preventing infectious diseases, there remain numerous globally devastating diseases without fully protective vaccines, particularly human immunodeficiency virus (HIV), malaria and tuberculosis. Nanotechnology approaches are being developed both to design new vaccines against these diseases as well as to facilitate their global implementation. The reasons why a given pathogen may present difficulties for vaccine design are unique and tied to the co-evolutionary history of the pathogen and humans, but there are common challenges that nanotechnology is beginning to help address. In each case, a successful vaccine will need to raise immune responses that differ from the immune responses raised by normal infection. Nanomaterials, with their defined compositions, commonly modular construction, and length scales allowing the engagement of key immune pathways, collectively facilitate the iterative design process necessary to identify such protective immune responses and achieve them reliably. Nanomaterials also provide strategies for engineering the trafficking and delivery of vaccine components to key immune cells and lymphoid tissues, and they can be highly multivalent, improving their engagement with the immune system. This Review will discuss these aspects along with recent nanomaterial advances towards vaccines against infectious disease, with a particular emphasis on HIV/AIDS, malaria and tuberculosis.

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According to the World Health Organization, HIV/AIDS, malaria and tuberculosis (TB) combined caused more than 2.5 million deaths worldwide in 2017, most of them occurring in low-income countries 1 , 2 , 3 , 4 . In resource-limited countries, these three pathogens are among the top 10 causes of mortality, highlighting the need to develop prophylactic strategies. Although HIV/AIDS, malaria and TB are caused by dissimilar pathogens, the challenges they present for vaccination share commonalities, and nanomaterials are uniquely positioned to address some of these challenges. One common feature is that in each, the immune response to infection does not generally result in protective immunity, in contrast to other vaccine-preventable diseases such as measles or varicella, which do generate protective immunity in most individuals. Because of this, successful vaccine strategies for HIV, malaria or TB must produce immune responses that are uniquely engineered to be distinct from that of natural infection. The synthetic origins of nanomaterials, along with their defined and tailorable structures and increasingly clear engineering design rules offer potential routes to such vaccines. A second commonality is that these three diseases impact tropical and developing locations of the globe most significantly, resulting in challenges of distribution and implementation. The synthetic composition of nanomaterials can also offer advantages in this regard. Third, for each of these diseases, a successful vaccine strategy will likely involve more complex immune responses than simple antibody production, potentially including engagement of a precise combination of humoral and cellular immunity. Here again, the multifunctionality and tailorability of synthetic and nanomaterial-based vaccines offers advantages. Finally, with the global health community currently responding to a pandemic caused by the novel coronavirus SARS-CoV2, the insights gained from vaccines against the infectious diseases described here may also be critical for developing a prophylactic vaccine for this pathogen.

This Review will focus on nanomaterial vaccines under development toward malaria, TB and HIV, emphasizing recent work and an emerging understanding of how such materials engage the immune system. Vaccines based on designed protein, peptide, lipid, polymer and inorganic nanomaterials will be discussed (Fig. 1 ). We will not address other areas of nanomaterials immune engineering such as anticancer immunotherapies, tolerance induction to treat autoimmunity, or other infectious diseases, despite intense interest in these areas and similar nanomaterials being explored. The reader is instead referred to other recent reviews in these sub-areas 5 , 6 , 7 as well as recent comprehensive reviews 8 , 9 , 10 , 11 .

a , b , Ferritin nanoparticle core decorated with gp140 HIV envelope proteins. c , d , Self-assembling protein nanoparticles displaying malaria epitopes. Scale bar, 100 nm. e , f , Self-assembled peptide nanofibres bearing malaria epitopes. Scale bar, 100 nm. g , h , Inter-bilayer crosslinked multilamellar vesicles with surface bound HIV envelope trimers and thiolated polyethylene glycol (PEG-SH). Scale bar, 20 nm. i , j , Fullerenol particles used as nanoadjuvants for a HIV-1 DNA vaccines. Scale bar, 100 nm. k , l , Liposomes incorporating nickel-binding (DGS-NTA(Ni)) and thiol-reactive (MPB) lipids covalently bound to HIV-1 trimers (MD39-HHHHHHC). Scale bar, 100 nm. Panels a and b adapted with permission from ref. 82 , AAAS. Panels c and d adapted from ref. 164 . Panel f adapted with permission from ref. 156 , Elsevier. Panel g adapted with permission from ref. 109 , American Chemical Society. Panel h adapted with permission from ref. 165 , Springer Nature Ltd. Panels i and j adapted with permission from ref. 153 , Wiley. Panels k and l adapted from ref. 148 , distributed under a CC BY 4.0 license ( http://creativecommons.org/licenses/by/4.0/ ).

Since the beginning of the HIV-1 pandemic, more than 30 million infected individuals have died. In 2017, 36.9 million people were living with HIV-1, including 1.8 million newly infected individuals, and HIV-1 was responsible for 940,000 deaths with 110,000 deaths occurring among children under 15 years of age 4 . It is well recognized that a vaccine is critically needed to contain the pandemic, yet despite over 30 years of research, a vaccine has not yet been developed successfully. Several virologic and immunological factors stand in the way of developing an effective prophylactic HIV-1 vaccine. One of these is that the highly dynamic HIV-1 genome, driven by its error-prone reverse transcriptase and recombination between its genome copies, represents a moving target for the design of an optimal vaccine immunogen. Moreover, as HIV-1 infected individuals are not able to eradicate the virus, there are no clear immune correlates of protection in humans. Early studies have demonstrated that the emergence of virus-specific CD8 + T cells in the acute phase of infection was coincident with viral control 12 and long term non-progressors have been reported to have potent, polyfunctional cellular immune responses 13 . However, elicitation of robust cellular responses does not provide the sterilizing immunity needed to prevent infection.

In a subset of individuals, antibodies that target vulnerable sites of the viral envelope (Env) incrementally develop neutralizing potency and evolve into broadly neutralizing antibodies (bnAbs) after several years of untreated infection 14 . These bnAbs have characteristics such as a high level of somatic hypermutation, long complementary determining regions 3 (CDR3) and poly-reactivity 15 , 16 . It has been shown that passive immunization with bnAbs can prevent viral acquisition in non-human primates 17 , 18 . While elicitation of broad neutralization is a priority in the HIV-1 vaccine field, designing vaccine immunogens capable of recapitulating the process of bnAb development has proven extremely difficult. This is in part due to the fact that some bnAb epitopes are shielded by the extensive, minimally-immunogenic glycan fence of the Env 19 . Moreover, the highly variable regions on the HIV-1 Env present as decoys, directing the humoral response away from the relative constant regions that are usually bnAb target sites 20 . Induction of bnAbs may also require breaking immune tolerance mechanisms 21 and may be dependent on follicular helper T cells (T FH ) 22 .

Compared to bnAbs, non-neutralizing antibodies are easier to elicit with vaccination and may provide modest protection against HIV infection, as exemplified in the RV144 vaccine efficacy trial conducted in Thailand 23 . In this trial, vaccinees were primed with a recombinant canarypox vector expressing HIV-1 Gag, Pro and Env antigens from subtypes B and E, and then boosted with an Env subunit vaccine adjuvanted with Alum 23 . The immune correlate analysis of this moderately efficacious vaccine trial indicated that IgG antibodies against the envelope variable loops 1 and 2 (V1V2) were associated with reduced risk of HIV-1 acquisition 24 , whereas high plasma levels of vaccine-elicited IgA were associated with increased HIV-1 acquisition, probably by mitigating the protective effect of IgG against the same epitopes 25 . Importantly, the mechanism by which V1V2 antibodies mediated protection is not fully understood. As the vaccine-elicited antibodies only neutralized minimally evolved (Tier 1) viruses 26 , it has been speculated that Fc-mediated, non-neutralizing antibody functions may mediate protection. In fact, monoclonal antibodies isolated from RV144 vaccines are able to mediate antibody-dependent cellular cytotoxicity 27 , and vaccine-elicited V1V2-specific antibodies can activate the complement cascade 28 . Nevertheless, the potential for protection of this vaccine approach is now uncertain, as a recent efficacy trial conducted in South Africa attempting to replicate the results of RV144 (HVTN 702) was halted prematurely due to the lack of efficacy 29 . In this trial, HIV-1 subtype C antigens were included in the vaccine in order to increase coverage against the virus strains circulating in South Africa, which has infection rates significantly higher than in Thailand. Whether differences in vaccine regimens, infection rates, or trial populations contributed to the differences observed between the two trials is still unclear 29 . Vaccination studies in non-human primates have also supported a protective role for non-neutralizing Fc-mediated effector functions 30 , 31 . Yet, studies in non-primates have indicated that passive immunization with non-neutralizing antibodies confer limited or no protection against virus acquisition 32 , 33 .

Achieving protective immunity against HIV-1 may require the elicitation of both robust antibody responses with the aim of blocking/reducing infection acquisition and effective cellular responses to control breakthrough infections. Similar to natural infection, immunization with monomeric Env vaccine immunogens can induce robust antibody responses against immuno-dominant epitopes, but these antibodies are unable to neutralize circulating virus strains 34 . Strategies being pursued to design B cell immunogens with the goal of inducing bnAbs include: immunogens that mimic the native Env structure such as virus-like particles (VLP) bearing only pure native functional Env proteins 35 , stabilized soluble immunogens that reproduce the trimeric structure of Env 36 , and bnAb epitope-focused immunogens 37 . Several approaches are also being pursued for the induction of effective T cell responses including immunogens targeting the most conserved regions of HIV-1 38 and mosaic immunogens, which are designed using computational approaches to generate combined protein sequences from multiple naturally-occurring proteins 39 . In addition to challenges in eliciting antibodies of protective specificities, immunization with HIV-1 Env constructs usually induces antibody responses of limited duration 40 . This issue, along with the need to engage multiple arms of the immune system to achieve protective immunity, makes synthetic and nanomaterial-based approaches attractive.

Malaria, like HIV-1, presents unique challenges for vaccination. While preventive measures have significantly impacted the incidence and severity of malaria infections, continued progress has been difficult to achieve. In 2017, 219 million cases of malaria occurred, 2 million more than in 2016, and the number of malaria-related deaths remained above 400,000 3 . Children under the age of five have been especially vulnerable, accounting for 61% of malaria-related deaths in 2017. Most are due to Plasmodium falciparum , which has a complex life cycle and exists in several forms in humans: sporozoites, which infect hepatocytes; merozoites, which infect red blood cells; and gametocytes that continue the life cycle in mosquitos, where they undergo sexual replication 41 . Because of this complexity, vaccines against each stage are currently being pursued 42 .

Following natural malaria infection, sterilizing immunity does not develop, so the immune response elicited by a successful vaccine must be distinctly different. The most advanced malaria vaccine candidate (RTS,S) contains the central repeat and terminal epitopes of the major surface antigen circumsporozoite protein (CSP) and has exhibited 43.9% efficacy after four immunization doses in children and 27.8% efficacy in infants 43 . However, efficacy quickly wanes and is variable among the paediatric populations studied 44 . Thus, there is a need for new strategies to improve efficacy and durability. Another major challenge is the lack of clearly defined correlates of protection, making target selection and formulation optimization challenging. Other hurdles include the complexity of the parasite, with hundreds of potential vaccine targets, the immune evasion inherent in its complex life cycle, the high level of polymorphisms in the most immunogenic antigens 45 , and poor immunogenicity of conserved epitopes 46 . Interestingly, in addition to anti-CSP antibodies, polyfunctional T cell responses may also contribute to protection against malaria. In fact, polyfunctional CD4 + T cell responses were associated with protection in individuals primed with the adenoviral vector Ad35-CSP and boosted with RTS,S 47 . In other studies, vaccine-elicited CD8 + T cell responses have also been associated with protection 48 . These results demonstrate that several branches of the adaptive immune system may need to be recruited to increase the efficacy of a malaria vaccine. Nanomaterial-based vaccines may thus help overcome some of these challenges by enhancing vaccines targeting conserved epitopes, by providing routes for engaging both humoral and cellular immunity, and by providing defined candidates whose design can be optimized systematically as correlates of protection are increasingly revealed.

TB infected 10 million individuals in 2017 and was responsible for an estimated 1.3 million deaths, making it the leading cause of mortality due to a single infection 2 . TB cases are complicated by the emergence of multi-drug resistant bacteria and frequent HIV co-infections. In fact, in 2017, 9% of new TB infections occurred in HIV-infected individuals, and TB was responsible for 300,000 deaths among HIV-infected patients 2 . Mycobacterium tuberculosis ( M. tuberculosis ) generally infects the lungs, but it can also infect extrapulmonary organs. Following primary infection, TB can evolve towards active disease, latent infection, or be eradicated by the host immune system. Macrophages constitute the first line of defence against TB, but the pathogen can successfully persist in macrophages. Another mechanism of immune evasion includes the transition into a dormant stage that is highly resistant to the host immune system and can persist for years within granulomas 49 . In young children, immunization with the live-attenuated Bacillus Calmette Guerin (BCG) vaccine can provide protective immunity against severe TB disease 50 , but the efficacy of this vaccine is low and it poorly protects from TB acquisition. Moreover, the BCG vaccine is less efficacious in adults and variable across different geographic settings 51 . Interestingly, a recent BCG vaccine study indicated that when immunized intravenously, 90% of macaques were protected against M. tuberculosis challenge, suggesting that it may be possible to broaden the efficacy of BCG vaccination 52 .

As with HIV and malaria, a major hurdle to the development of an effective TB vaccine is the lack of well-established immune correlates of protection and an incomplete understanding of protective mechanisms 53 . IFN‐γ producing CD4 + T cells are thought be critical for TB control, but this response may not be sufficient to induce protection. Other T cell subsets including CD8 + T cells and unconventional T cells subsets such as HLA-E restricted CD8 + T cells may also contribute to protection, but their role is not yet clearly established. There are currently multiple ongoing TB vaccine clinical trials. Two subunit vaccines showing promising effects include M72/AS01 E and H4:IC31 54 . M72/AS01 E , which consists of a recombinant fusion protein (M72) of two M. tuberculosis antigens with the AS01 liposomal adjuvant system, was shown to protect 54% of adults in a study of individuals with latent TB infection 55 . H4:IC31 consists of a recombinant fusion protein (H4) of three M. tuberculosis antigens with the IC31 TLR-9 agonist adjuvant system. In a study of adolescents previously vaccinated with BCG, both H4:IC31 or a secondary BCG vaccination were shown to reduce the rates of persistent TB infection 56 . Most current TB vaccine candidates are designed primarily to induce cellular immune responses. However, whether these vaccines will be able to elicit the sterilizing immunity required to prevent acquisition is not yet completely clear. The development of a TB vaccine is further complicated by the fact that M. tuberculosis expresses about 4,000 proteins at levels that vary with the metabolic stage, complicating antigen selection 57 . Nanomaterials that can carry multiple antigens are therefore of interest for TB vaccine development, and they are further appealing because they can provide adjuvant effects required to tune the immune response towards potentially important mechanisms such as elicitation of Th1 responses.

Mechanisms by which nanomaterials improve vaccine responses

A central aspect in the engineering of nanomaterial vaccines against HIV, malaria and TB involves their delivery to key cells and tissues of the immune system. However, unlike other drug delivery applications that may target a narrowly defined cell type, a productively immunogenic nanomaterial vaccine needs to interact with many different types of cells. These may include various professional antigen presenting cells (APCs), B cells, macrophages, neutrophils and T cells of various types after the vaccine-associated antigens have been processed. These interactions occur across extended time periods, in multiple tissue locations and after considerable processing, making it a complicated endeavour to rationally engineer the trafficking of a nanomaterial vaccine (Fig. 2 ). Features under control can include the size and shape of the nanomaterial, its durability in vivo, the number of antigen copies on or within the nanomaterial, the specific co-delivery of adjuvants, the physical orientation of antigens, or complement activation. Each of these factors influences how the vaccine traffics to various lymphoid tissues, with considerable impact on the quality and strength of immune responses raised. These aspects are discussed in this section.

Lymph node (LN) trafficking: nanomaterial trafficking to lymph nodes is largely dependent on size but is also influenced by charge, hydrophobicity, flexibility and other physical properties. Mucosal Targeting: to induce mucosal immunity, nanoparticles must be able to penetrate mucosal barriers. Hydrophilic polymeric coatings limit entanglement with mucin fibres, and positively charged nanoparticles are mucoadhesive. Persistence: nanoparticle persistence prolongs the release of antigen, allowing for greater antigen uptake by APCs over time. Examples of nanoparticle persistence include depots present at injection sites or in the draining lymph nodes. Controlled Release: the controlled release of antigens from nanoparticles can take many forms. Endosomal escape is illustrated here with polymeric nanoparticles being endocytosed and then degraded in the endolysosomal pathway. As the polymer degrades, it disrupts the endolysosomal membrane, which allows for release of antigen into the cytoplasm. Cross presentation of the antigen on MHC I ensues. APC Targeting: there are several methods for targeting APCs. DCs can be targeted via receptors such as DEC-205. Macrophages have been shown to preferentially phagocytose anionic nanoparticles. B cell receptors recognize B cell epitopes on the surface of nanomaterials, and uptake is facilitated by multivalency. MØ, macrophage.

Encapsulation or conjugation of antigens within nanomaterials can greatly increase the persistence of antigens at the injection site, in the circulation, in lymphoid tissues, or even within APCs (Fig. 2 ). It has long been appreciated that extending the persistence of an antigen can enhance its immunogenicity, and a variety of nanotechnological strategies for achieving this have been explored. For example, Moon et al. demonstrated that interbilayer-crosslinked multilamellar vesicles (ICMVs) with both encapsulated and surface-conjugated malaria antigens can improve vaccination compared with the soluble antigen, owing to the prolonged presence of the antigen in the draining lymph nodes (LNs) 58 . Demento et al. similarly illustrated the effect of prolonged antigen delivery using poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating ovalbumin as a model antigen 59 . The prolonged release of antigen allowed for improved immunogenicity, and the degradation rates of the PLGA nanoparticles could be manipulated to further extend the ovalbumin release. The slowly degrading nanoparticles served as a durable source of antigen for APCs to acquire and present to follicular helper T cells (T fh ), which play a central role in germinal centre reactions in LNs, where antibody affinity maturation takes place. This process of generating high affinity antibodies to vaccine targets is critical for generating protective immunity against infectious diseases.

Although the creation of depots at injection sites can help prolong antigen exposure and facilitate germinal centre reactions, strong cellular immune responses still require that antigens be internalized, processed and presented efficiently by APCs. In order to mount a specific cytotoxic CD8 + T cell response against HIV, TB, or Malaria, cross-presentation of their exogenous antigens on class-I MHC must first be achieved. For successful cross-presentation to be achieved, antigen fragments must further escape to the cytosol. To accomplish this, nanomaterials sensitive to the environment of the endolysosomal pathway have been explored. This strategy mimics some viral infections and enables enhanced CD8 + T cell responses compared to the delivery of free antigen 60 . For example, Hirosue et al. demonstrated that when ovalbumin peptide antigens were linked to the surface of pluronic-stabilized poly(propylene sulfide) (PPS) nanoparticles via disulfide bonds that were cleavable in the reductive environment of the endolysosomal pathway, cross presentation was enhanced compared to antigens attached via non-reducible linkages 61 .

The controlled and predictable delivery of nanoparticle vaccines to the large population of B cells, T cells, follicular dendritic cells, and subcapsular sinus macrophages residing in the LNs is highly sought for vaccine design. While antigens can be delivered to the LNs via APCs that acquire the antigens at the injection site and migrate to the LNs, drainage to the LNs also occurs, largely dependent on the size of the nanoparticles (Fig. 2 ). With the caveat that multiple physical properties of nanoparticles influence lymphatic drainage, including charge, shape and flexibility, it has been observed that nanoparticles smaller than 100 nm tend to drain to the LNs, with 10–50 nm being near the optimal size 62 , whereas those close to 6 nm or smaller tend to drain to the vasculature 63 . The larger the nanoparticles were within this range, however, the better they were retained in the LNs 64 . Larger nanoparticles that passively drained to the LNs were acquired by subcapsular macrophages, while smaller particles were more likely to enter conduits and travel to B and T cell zones 65 . Beyond size, characteristics such as flexibility can also influence the drainage of nanoparticles to LNs 66 , and different nanomaterial platforms may have subtly different optimal sizes for lymphatic drainage. Intranodal injection, though invasive, volume limiting and subject to rapid clearance via afferent lymph, may begin to circumvent such considerations altogether 67 , 68 , 69 .

In the case of respiratory, sexually and orally transmitted pathogens such as TB and HIV, the mucosal immune response is particularly relevant, so mucosal delivery of nanomaterials has received particular attention (Fig. 2 ). Mucus is a porous network of mucin glycopoymers 70 , 71 , and the ability of nanoparticles to pass through or adhere to it is largely dependent on size and surface characteristics. Pore sizes vary within different mucosal barriers, with cervicovaginal mucus reported to have average pore diameters of 340 nm 72 and respiratory mucus up to 200 nm, so nanoparticles smaller than these cut-offs can traverse these barriers more easily 73 . Hydrophilic polymers such as poly(ethylene glycol) (PEG) have also been found to greatly facilitate transit of particles across the mucus layer (see Box 1 regarding immunological considerations of PEG in nanomaterials) 80 , 83 , 84 . Additionally, cationic nanoparticles are mucoadhesive, allowing them to be retained in the mucus and giving them a greater opportunity to interact with mucosal immune cells. Chitosan, a cationic polysaccharide derived from the shells of crustaceans, has been employed in mucosally delivered vaccine nanoparticles 74 , including those against TB 75 .

Beyond targeting LNs or mucosal tissues, considerable work has been undertaken to direct the uptake of nanoparticles to specific subsets of APCs (Fig. 2 ). In many sites of delivery, nanomaterials are avidly acquired by macrophages owing to their broadly phagocytic nature. Although the design rules for achieving cell-type-specific uptake are multifactorial and interdependent, nanoparticle size, charge and shape can be manipulated to enhance macrophage uptake or to favour uptake by other APCs 76 , 77 . For example, it has been reported that macrophages preferentially ingest anionic particles 78 , whereas both DCs and macrophages can be passively targeted based on nanoparticle size, with particles from 20–200 nm being endocytosed by DCs and particles from 500–5,000 nm being phagocytosed by macrophages in some contexts 79 . Specific receptors on DCs also provide opportunities for affinity-based targeting strategies of specific DC subsets 80 . These include C-type lectin receptors such as DEC-205 and DC-SIGN, which are heavily expressed on epithelium-resident Langerhans cells and LN-resident DCs 81 . Other strategies have targeted follicular dendritic cells (FDCs) in LNs. Multivalent ferritin nanoparticles displaying HIV antigen glycoproteins targeted FDCs and enhanced the development of germinal centres, discussed in greater detail in the section below on multivalency 82 . B cells, another important APC in the context of nanomaterial based vaccines, can be targeted by repetitive, multivalent antigen structures, which cross-link B-cell receptors and lead to enhanced uptake and activation 83 , also discussed in greater detail in the next section.

Nanomaterial vaccines also offer routes to improve the function of adjuvants and to minimize negative systemic or local effects such as inflammation or toxicity. Dosing adjuvants so as to achieve strong immune responses without such negative effects is a persistent challenge in vaccine design 84 , 85 , and the delivery of adjuvants via nanomaterials can provide routes towards dose reduction by controlling adjuvant release near or inside APCs 86 . For instance, Moon et al. demonstrated that multilamellar ‘stapled’ lipid vesicles incorporating a malaria antigen and delivered in combination with the TLR4-agonist adjuvant MPLA allowed for a 10-fold dose reduction of the adjuvant when compared to a soluble antigen/MPLA vaccine and induced more diverse humoral responses 57 . Other adjuvanted lipid nanomaterial formulations have also been shown to raise higher antibody titers than simply mixing antigen with adjuvant 87 . As another example, Huang et al. demonstrated that His-tagged Pfs25 malaria antigens inserted into the lipid bilayer of adjuvant-encapsulating liposomes generated durable antigen-specific plasma cells 88 . Furthermore, some nanoparticles have intrinsic adjuvanting properties, even without augmentation by TLR ligands or other adjuvants. Pathways by which this may occur include complement activation, inflammasome signalling or B cell activation 8 . Such intrinsically adjuvanting nanoparticles may be advantageous because they can limit inflammation and toxicity arising from other adjuvants, and they simplify the formulation and dosing of a vaccine.

Box 1 A note about polyethylene glycol in nanomaterial vaccines

A longstanding strategy for modulating the delivery of biologics and nanomaterials, polyethylene glycol (PEG) was originally regarded as a nonimmunogenic polymer, but recent findings have revealed more complexity surrounding PEG immunogenicity. One study showed that among 377 people not previously exposed to a PEGylated drug, about 72% of them had at least low levels of pre-existing anti-PEG antibodies 167 . However, the implications of anti-PEG antibodies continue to be debated. The sensitivity and specificity of different assays for detecting anti-PEG antibodies vary considerably, making reliable measurement and comparison between studies challenging 167 , 168 . Currently, the use of PEG in nanomaterial vaccines must be optimized for each specific vaccine context in light of the potential range of responses that are possible, as PEGylation can have either pro-immunogenic 169 or anti-immunogenic 170 effects in different vaccine systems. Moreover, the ultimate consequence of any anti-PEG antibodies raised will depend considerably on antibody characteristics such as titer, affinity, isotype and polyclonality. Currently there is much progress left to be made in fully unravelling the mechanisms and context-dependent ramifications of PEG immunogenicity in nanomaterial vaccines.

The impact of multivalent protein display by nanomaterials

Spatially repetitive structures are intrinsic to viruses, bacteria, and other pathogens, and the immune system has evolved to recognize and respond to them with exquisite sensitivity. Many viruses and bacteria contain repetitive antigens spaced at around 5-10 nm apart 89 , yet notably some pathogens have evolved to minimize such structures. For example, the envelope spikes of HIV are fewer and more separated than on other spherical viruses, leading to the hypothesis that the virus has evolved specifically to minimize the effects of multivalency, even at a cost of its transmissibility 90 . Thus, the ability to finely manipulate, enhance and optimize antigen density and orientation is one of the most advantageous features of nanomaterials (Fig. 3 ), because such control is more difficult to achieve in other forms of vaccines. As evidence of the power of multivalency in nanomaterial vaccines, several highly repetitive structures have been found to elicit strong humoral and cellular immune responses even without supplemental adjuvants or other immunostimulating components. This property is exhibited by supramolecular peptide assemblies 91 , 92 , 93 , 94 , 95 , self-assembled polypeptide nanoparticles 96 , 97 , and other multivalent particulates 62 , 98 , but it is less common for purely soluble proteins. The effect of multivalency is so powerful that even epitopes that would otherwise be tolerized, such as those within autologous cytokines, can be made immunogenic 95 .

Multivalent displays of proteins, carbohydrates and B cell epitopes activate immune cells through a variety of pathways. a , Several modes of immune cell engagement occur via complement activation through binding of complement protein C3 or its cleavage product C3b to nucleophilic groups on surfaces and polymers, or by binding of ficolin or mannose-binding lectin to carbohydrates. Complement activation leads to association of C3d and C3b with nanomaterials, which bind to complement receptors 1 (CR1) and 2 (CR2), respectively. b , Activation of complement causes nanomaterials to be shuttled to follicular dendritic cells, where they can be displayed for long periods of time 82 . c , Macrophages in the subcapsular sinus also capture particulate antigens and transfer them to follicular B cells in a complement-dependent manner 166 . Both b and c are processes that drive affinity maturation. d , Multivalent particles can also activate B cells directly by crosslinking B cell receptors to increase uptake and activation by signalling through immunoreceptor tyrosine-based activation motifs (ITAMs) 103 .

Defined materials offer the opportunity to investigate the structural features and immunological mechanisms that lead to the immunogenicity-enhancing effects of multivalency. Early work by Howard and Renee Dintzis and co-workers with multivalent polymer-conjugated dinitrophenyl haptens demonstrated that such materials were able to activate T-independent B cell responses 99 . In a series of landmark studies, it was demonstrated that repetitive displays of polymer-linked haptens were able to activate immune cells in a fashion that was dependent on molecular weight, ligand density and ligand number 99 , 100 , 101 . This phenomenon is quantized, and a critical number of hapten molecules are required to produce a T-independent antibody response 100 . For example, for polyacrylamide-linked haptens, a sharp threshold of immunogenicity was observed when more than 12–16 copies of the hapten were conjugated to the polymer. Higher molecular weight polymers with a lower density of ligands could also crosslink receptors because of the polymers’ flexible backbones 100 . Notably, the phenomena described were distinct from the processes by which nanoparticle vaccines typically raise immune responses, as these generally contain T-cell epitopes and raise T-dependent responses, yet multivalency still facilitates T-dependent processes as well 102 . Though these examples utilize model epitopes, they shed light on the mechanisms by which nanomaterials raise immune responses.

Particulate displays of antigen, such as those created by conjugating antigens to nanoparticles, promote uptake by B cells even if their BCRs have low affinity for the antigen. Work by Batista and Neuberger demonstrated that linking hen egg lysozyme (HEL) to the surface of beads allowed equal levels of uptake and presentation by high- and low-affinity B cells, whereas the uptake of soluble proteins was correlated to the affinity of the BCR for HEL 103 . The authors speculated that this was due to increased avidity interactions when multiple BCRs were crosslinked, lowering the upper limit for B cell discrimination between high- and low-affinity BCR–antigen interactions 103 . In agreement with the quantized model proposed by Dintzis, this effect was conserved for multiple levels of antigen density, then dropped off at a lower threshold of antigen density 103 . Activation of B cells with multivalent antigen displays can be particularly useful for engaging B cells with low affinity BCRs for vaccination against autologous targets 95 , 104 , or for the engagement of HIV bnAb precursors with low affinity to the antigen 37 .

Kiessling and co-workers used highly defined polymeric systems to investigate how multivalent hapten displays influenced multiple steps of B cell internalization and activation to produce functional antibody responses 105 . Polymers containing 500 hapten molecules per polymer chain induced higher levels of antibodies than polymers with 10 haptens per chain and correlated with increased BCR clustering and intracellular Ca 2+ signalling but did not significantly influence polymer internalization 105 . This work was then extended to incorporate T-cell epitopes, finding that B cells functioned as important APCs for polymer constructs of immunogens 106 . The ratio of B cell epitope to T cell epitope has also been shown to significantly impact antibody titers against B cell epitopes in self-assembling peptide systems 95 , 107 . While the exact mechanism of this phenomenon is still not completely understood, it is becoming clear that B cell epitope density is critical both for the activation of B cells and for their role as APCs in coordinating humoral and cellular immune responses. For example, recent work has shown that B cells are the key APCs for orchestrating immune responses to VLPs and can function independently of dendritic cells to generate germinal centre responses 108 .

The effects of nanomaterial-multimerized antigens on antibody repertoire have been observed in several infectious disease vaccine design settings. Tethering the Plasmodium vivax circumsporozoite antigen VMP001 to multi-layered liposomes improved the avidity, durability and breadth of antibody responses compared to soluble antigen when adjuvanted with the Toll-like receptor (TLR) agonist MPLA 58 . HIV trimers tethered to liposomal carriers induced antibodies against more regions on the target antigen 109 and more HIV viral proteins 110 compared to non-multimeric vaccines. This increase in antibody breadth was hypothesized to be caused by activating a more diverse set of B cells by clustering relatively low-affinity BCRs.

Recently, self-assembling two-component protein nanoparticles have been utilized for the display of viral antigens to elicit immune responses against strategically displayed B cell epitopes 111 , 112 . These particles also allow for detailed study of how the number of antigens affects immune response, as varying ratios of assembling components can be expressed without an antigen. Although not directed against TB, HIV or malaria, the work is illustrative, as increasing copies of antigen per particle were shown to improve neutralization of viral strains after immunization with the RSV antigen DS-Cav1. More highly multivalent particles also enhanced the numbers of T FH cells and germinal centre B cells 111 . Fully decorated particles, bearing 20 copies of DS-Cav1 promoted neutralizing antibody responses 10-fold higher than soluble DS-Cav1 111 , demonstrating the potential for highly multivalent nanoparticle vaccines to elicit protective immune responses.

Recent work with multivalent HIV nanovaccines has shed light on some of the mechanisms by which repetitive antigen presentation enhances the retention of vaccine particles within germinal centres and improves B cell activation compared to soluble proteins (Fig. 3 ) 82 , 110 . Recently Tokatlian, Irvine and co-workers demonstrated that immune responses to multivalent protein nanoparticles were complement-dependent and significantly influenced by the repetitive displays of glycans on the particle surface 82 . They illustrated that multivalent saccharides promoted the binding of mannose binding lectin (MBL), which subsequently induced complement-dependent trafficking of the particles to the follicular dendritic cell network within LNs. This shuttling led to an increased association of antigen with follicles and induced higher numbers of germinal centre B cells. In other work, conjugation of trimannose groups to polystyrene nanoparticles facilitated shuttling of these materials to follicles 82 . This articulation of a key mechanism of nanomaterial multivalency now enables the engineering and optimization of this process using carefully controlled patterns of saccharides on the materials’ surfaces.

Despite the marked improvements endowed by nanomaterials in many examples, some authors have reported minimal improvement of immune responses in other situations 113 , 114 . Based on the studies described above, it appears likely that fine adjustments of protein density, spacing and orientation coupled with optimized saccharide identity and arrangement will be key aspects determining the level of success of this approach.

Beyond delivery aspects and multivalency, the tethering of an antigen to a nanomaterial surface affords the opportunity to orient the antigen in a strategic way. By burying undesirable epitopes and exposing choice epitopes, the resultant antibody response can be shaped. Being able to influence the epitope specificity of vaccines presenting folded proteins is critical for minimizing responses to immunodominant, non-neutralizing regions of antigens, such as the base and V3 loop tip of HIV trimers 115 . The use of nanomaterials to alter protein display has been utilized for vaccines against Epstein–Barr virus (EBV) 113 and has recently been exploited by screening for protein displays that bind neutralizing antibodies 116 . By tethering the EBV antigen gp350 to a ferritin or encapsulin core, antibodies were directed to a desired binding site to interfere with the virus’s ability to bind its target, complement receptor 2 on B cells, thus significantly improving neutralization compared to a soluble control. 113 To screen for vaccine materials that would induce neutralizing antibodies, Bazzill et al. used a method termed NanoFACS to demonstrate that neutralization capacity of various protein–nanoparticle vaccines could be predicted by their binding to neutralizing antibodies in vitro, which likely varied according to the orientation of the protein on the particle surface 116 .

The impact of protein orientation was also demonstrated by Martinez-Murillo et al. when HIV trimers were presented in high density on the surface of liposomes 117 . Similar to other nanoparticle vaccines, vaccines based on liposomes increased the size of germinal centres and the average number of T FH cells contained within each germinal centre 117 . Interestingly, the antibodies produced by an animal with high Tier 2 neutralization showed a unique mode of binding to the trimer, resembling the binding displayed by bnAb VRC01 117 . Tier 2 indicates viruses moderately sensitive to neutralization, is typical of most circulating strains, and is a high priority for vaccination. This binding, characterized by horizontal access to the V2 cap, is not typically observed in antibodies elicited by soluble trimer vaccines, and it indicated that presentation of antigen on multivalent surfaces may direct the antibody response towards antigenic regions, which are typically sub-dominant 117 . Another system in which epitope accessibility can be controlled is the two-component protein nanoparticles described above 112 . This structural tailoring directly influences the specificity of antibodies toward surface proximal epitopes, as epitopes closer to the base are masked by other components of the nanoparticle 112 . Similar strategies to orient antigens have been based on multimerizing proteins such as ferritin, virus-like particles, and other de novo proteins 118 , 119 , 120 .

Examples of nanomaterial vaccines for infectious diseases

In this section, we will describe nanomaterials of various classes and provide examples how each are being employed towards vaccines against HIV, TB and malaria. Many of these vaccines make use of the mechanisms and design aspects discussed previously.

To design vaccines capable of maximally engaging the immunological processes sensitive to multivalency, many approaches for arraying antigens on surfaces have received intense interest, with self-assembling protein nanoparticles being among the most promising class. Ferritin, a protein utilized by most living organisms for iron storage, assembles into a 24-member spherical cage structure (Fig. 1a ). Antigen–ferritin fusion proteins can form spherical nanoparticles with the antigens displayed on the particle surface in a multivalent fashion 121 . Multimeric proteins, such as trimeric HIV-1 Env, can be presented on the particles’ surface as well, with eight multimers displayed per particle. Such particles have improved immunogenicity compared to soluble trimers alone 122 . As discussed in the section ‘The impact of multivalent protein display by nanomaterials’, ferritin nanoparticles were recently employed to demonstrate that multivalency facilitated the trafficking of HIV native-like Env trimers to the follicular dendritic cell regions in draining LNs, likely through the activation of the complement system via the mannose-binding lectin pathway 82 . Display of HIV Env trimers on ferritin nanoparticles also showed increased immunogenicity in mice and rabbits, inducing higher neutralizing antibody responses including against the autologous Tier-2 virus 122 . While this strategy has not yet been shown to induce broad neutralization, the results are encouraging and warrant further exploration of similar approaches for elicitation of bnAbs. Recently, Saunders and co-workers used SOSIP trimers displayed on ferritin nanoparticles to select for B cell clones that share BCR mutations with bnAb precursors 123 . This study demonstrated significant progress in designing immunogens that could be capable of inducing bnAbs when viral antigens are displayed on nanoparticle surfaces.

Other examples of multimerized protein self-assemblies include those employing IMX313, an oligomerizing domain based on chicken complement inhibitor C4b-binding protein 124 . IMX313 spontaneously forms soluble seven-member assemblies with each subunit carrying a fused antigen. This system has been explored towards the design of vaccines against malaria 124 , 125 , 126 and TB 127 , 128 . For example, the malaria sexual stage antigen Pfs25 was fused to IMX313, forming heptameric protein nanoparticles. Antibodies induced by the Psf25-IMX313 nanoparticles were durable and capable of binding native antigen expressed on malaria ookinetes 125 . Moreover, in the presence of adjuvants, IgG purified from Psf25-IMX313-immunized mouse sera was more capable of blocking the formation of oocysts in mosquitos compared to IgG from Psf25-immunized mouse sera. Advantages of the IMX313 system are the small size of the oligomerizing domain (55 amino acids) and encouraging safety data in humans 128 .

Because ferritin can display 8 trimers or 24 subunits, and IMX313 can display seven subunits, larger particles with greater numbers of subunits are also being explored, including dihydrolipoyl acetyltransferase (E2p) and lumazine synthase (LS), both of which form 60-member spherical structures. Towards HIV vaccination, after designing a novel immunogen to induce VRC01-class bnAbs based on a minimal, engineered outer domain, Schief and co-workers fused their designed antigen to lumazine synthase 120 . The protein was expressed in mammalian cells with good yield and self-assembled into 60-member spherical nanoparticles 120 . The monomeric form of their designed antigen, eOD-GT6, failed to activate germline or mature B cells bearing VRC01 IgM, even though it bound germline VRC01 with K D below 50 nM, but the LS-based nanoparticles potently activated the VRC01 IgM germline and mature B cells 120 . The examples of ferritin, IMX313, E2p, and LS indicate that multimerization on a protein particle can have powerful effects on immunogenicity. It remains to be seen what spacing, number of antigens and particle sizes will maximize protective responses in the various contexts under investigation.

VLPs are non-infectious, non-replicating virions that resemble viruses in structure but lack a viral genome 129 . Over the past few decades they have contributed tremendously to vaccine development and have been reviewed comprehensively 130 , 131 , so they will be discussed briefly here in the context of the diseases of interest. A wide variety of virus families have been used to construct VLPs, and like the oligomerizing proteins previously discussed, antigens presented by them can retain their native conformation, allowing for multivalent antigen presentation. Owing to successful clinical translation in the form of licensed vaccines against human papilloma virus, hepatitis B and E, and influenza, VLPs make attractive candidates for further development as vaccines against HIV, TB and malaria. In fact the first licensed malaria vaccine, RTS,S, is VLP-based, employing the hepatitis B surface antigen platform 119 . In a recent example of VLP design for HIV vaccination, HIV Env proteins displayed on VLPs have been shown to activate B cells producing the bnAb VRC01 in vitro 132 . McCurley et al. employed a sequential vaccination regimen on macaques with a series of VLPs displaying different HIV Env proteins to mimic the natural developmental pathway of the CH505 bnAbs 133 . Although this experiment failed to induce bnAbs, half of the vaccinated animals developed antibodies that neutralized the autologous tier 2 virus with a neutralization mechanism similar to CH505. Advantages of VLPs include their long track record of successful development towards many different diseases and well-established expression protocols. Self-assembled protein nanoparticles (Fig. 1c ) 96 , 97 , which have been designed using predictably oligomerizing coiled coil domains, have also been explored towards vaccines against malaria 96 , 97 , 134 . When self-assembled protein nanoparticles bearing B- and CD8 + T cell epitopes from the P.falciparum circumsporozoite protein and the universal CD4 T helper epitope PADRE were delivered in saline without adjuvant, high-titer, long-lasting protective antibody responses were observed against P. berghei infection in a rodent model 134 .

Polymeric materials have received interest as non-protein-based vaccine platforms owing to their advantages of being straightforward to synthesize and generally non-immunogenic by themselves (Box 1 ). Numerous types of polymeric materials have been investigated, including chitosan, polyesters such as PLGA and polyamides such as gamma polyglutamic acid (γ-PGA). In addition to nanoparticles, polyelectrolyte multilayers (PEM) and dendrimers have received interest for vaccine delivery. These have been reviewed elsewhere as well 135 , 136 .

Hydrolysable polyesters such as PLGA have been employed within nanomaterials to encapsulate protein antigens along with adjuvants 137 , 138 . PLGA encapsulation offers a number of advantages, including the ability to co-deliver multiple antigens or adjuvanting molecules such as TLR ligands in a prolonged fashion. In engineered vaccines requiring shaping of the immune response beyond that which is elicited during natural infection, this property is advantageous. For example, Pulendran and co-workers recently showed that encapsulation of simian immunodeficiency virus (SIV) antigens and multiple agonists for TLR7/8 and TLR4 within PLGA nanoparticles induced robust and durable antigen-specific antibody responses in macaques 139 . Interestingly, macaques immunized with the PLGA-encapsulated SIV vaccine had higher levels of protection against repeated, low-dose vaginal challenges with a heterologous SIV strain than animals immunized with SIV antigens adjuvanted with Alum. Nevertheless, one challenge with using PLGA as a vaccine carrier is that solvents utilized during the production of particles may potentially denature antigens and diminish their antigenicity. To address this issue, a ‘self-healing encapsulation’ technology was recently developed to allow the antigens to be loaded in a relatively mild, aqueous condition. Bailey and colleagues showed that ovalbumin delivered by this nanoparticle can induce strong CD8 + T cell and antibody responses 140 , 141 .

Polymeric nanoparticles have also been used to deliver DNA vaccines, where delivered genetic material leads to antigen expression in vivo, in strategies to increase immunogenicity and half-life. For example, polyamides such as γ-PGA have been utilized to design a plasmid DNA vaccine encoding the erythrocytic stage malarial antigen merozoite surface protein-1 (MSP-1) 142 . Chitosan has also been utilized for DNA vaccines, as it can complex with DNA and protect it from nuclease degradation 143 . DNA coding for T cell epitopes from the TB antigen early secretory antigenic target-6 (ESAT-6) encapsulated in chitosan nanoparticles induced higher T cell functionalities, including cytokine secretion and cytolytic activity, compared to the Bacillus Calmette–Guérin (BCG) vaccine, and offered greater resistance to infectious challenge 144 . Chitosan nanoparticles have also been used to increase immune responses at mucosal sites, in order to improve pulmonary immunity against TB 75 . Although linear polymers are commonly used within nanomaterials for vaccine delivery, highly branched structures such as dendrimers have also been explored. Strikingly, a single dose of dendrimer-encapsulated mRNA encoding viral surface antigens conferred protection against influenza, Ebola virus and toxoplasma gondii, an approach that may be applicable to HIV, malaria or TB 145 .

Other uses of polymers as nanostructured vaccines include polyelectrolyte multilayers (PEM), where layered structures are created with macromolecules of alternating charge. PEM construction occurs in mild aqueous conditions suitable for biomolecular cargos, and depending on the method used, nanoparticles or films can be produced 146 , 147 . For example, DeMuth and colleagues reported a microneedle array iteratively coated by layers of SIV gag-expressing plasmids and poly (I:C) as the adjuvant. After administration to mouse skin, the microneedle vaccine induced a potent CD8 + T cell response and antibody responses 10 times higher than injection/electroporation 147 .

As with polymer-based nanocarriers, liposomal delivery systems allow for the combination and co-delivery of multiple antigens and adjuvant molecules. They also offer opportunities to adjust size, charge, number of antigen copies and other physical parameters that influence trafficking and the immune responses elicited. As emphasized throughout this Review, such properties are especially beneficial for infectious diseases with unclear immune correlate for protection such as HIV, malaria and TB, because they allow iterative engineering of the vaccine. Further, liposomes allow for antigen to be displayed on the surface of a membrane, which for some antigens may be more representative of native conformations on viral particles, and there is sufficient surface area for the display to be highly multivalent, capitalizing on the mechanisms discussed above. Successful adjuvant systems based on liposomes have included AS01, used for example as part of the RTS,S and M72/AS01 E malaria vaccines 55 . AS01 contains in addition to liposomes the saponin QS-21 and the TLR-4 agonist 3-O-desacyl-4′-monophosphoryl lipid A. The ISCOMATRIX system also has similar components (phospholipids, saponins and cholesterol) and forms particulate assemblies on the order of 50 nm 114 . Designed lipid-based nanomaterials have built on the properties of these previous adjuvants by tailoring the assembly of antigens within them. For example, HIV Env trimers presented on interbilayer-cross-linked multilamellar vesicles (ICMVs, Fig. 1g,h ) could induce IgG against a conserved epitope on the trimer close to the HIV envelope membrane termed the membrane-proximal external region (MPER), whereas such IgG was not induced in animals immunized with the soluble trimer 109 . In a separate study, Env trimers formed a well-ordered high-density array on liposomes, resulting in not only higher levels of B cell activation but the production of neutralizing antibodies against neutralization-resistant HIV strains (tier 2) in rodents 110 . As mentioned above, ICMVs have also been employed by Moon and co-workers to design a recombinant malaria vaccine using the antigen VMP001 58 . Liposomal enhancement of humoral responses may result from increased germinal centre formation, because higher numbers of germinal centres and antigen-specific T fh cells were found in mice immunized with the ICMV vaccines.

Two additional advantages of liposomal nanomaterials include the ability to incorporate multiple antigens and the ability to tune and study the effects of vesicle stability. As an example of the former, Huang, Lovell and co-workers developed a liposomal vaccine platform where cobalt porphyrin-phospholide (CoPoP) was incorporated within the lipid membrane, so antigens expressed with a polyhistidine tag could be coupled to the liposomal surface 88 . They demonstrated that malaria Psf25 coupled to liposomes containing CoPoP and a TLR4 agonist could induce higher magnitudes of malaria oocyst-blocking antibodies than Psf25 adjuvanted with Alum. This platform then was explored with multiple antigens coupled to the liposomes, raising balanced responses against the antigens Pfg27, Pfs25, AMA-1, Psf30 and NANP, which are expressed in different stages of the malaria life cycle. Immunization with the same combination of antigens using Alum only induced antibodies against Pfs230. The authors surmised that the balanced multi-antigen response may have related to the low antigen dose used in the liposomal formulations or improved antigen uptake by APCs. To study how vesicle stability influenced immunogenicity against stabilized HIV gp140 trimers (BG505 MD39), Tokatlian, Irvine, and co-workers investigated synthetic liposomes variously incorporating sphingomyelin (Fig. 1k,l ), which augmented both the stability of the liposomes and germinal centre and antibody responses 148 .

Gold nanoparticles, with their control over size, shape and surface properties, have received interest as vaccines 149 . For example, Kumar and colleagues developed malaria transmission-blocking vaccines based on the sexual stage antigen Pfs25 conjugated to gold nanoparticles 150 . The vaccine constructs were stable at 4°C over an 18-month period, and mice immunized with the nanoparticle-conjugated-Pfs25 vaccines developed robust antibody responses. Interestingly, the immunogenicity and IgG subclass distribution of the vaccine-elicited antibodies varied with the size, shape and other physico-chemical properties of the nanoparticles, with only some nanoparticle formulations able to achieve antibody titers comparable to that of mice immunized with Alum-adjuvanted Pfs25.

Gold nanoparticles modified with viral glycans can also serve as dendritic cell-targeting vaccine carriers, facilitating antigen presentation to T cells and thus inducing more potent cellular antiviral immunity. In the context of HIV, Climent and colleagues engineered gold nanoparticles with high-mannoside derivatives that resemble the N-linked high-mannose glycan clusters on HIV gp120 targeted by DC-SIGN receptors on DCs. They pulsed monocyte-derived dendritic cells isolated from HIV-positive patients with HIV antigen gag p17 conjugated onto the high-mannoside-modified gold nanoparticles, finding that the nanoparticulate formulation induced more potent ex vivo proliferation of the autologous CD8 + T cells than soluble antigen 151 .

Other inorganic nanoparticles have also been used in TB and HIV vaccine development. Yu and colleagues developed an Ion (III) oxide (Fe 2 O 3 )-coated plasmid DNA TB vaccine expressing two immunodominant antigens of M. tuberculosis (Ag85A and ESAT-6) along with IL-21 152 . Compared to the naked plasmid DNA, the NP-coated vaccine induced greater humoral and cellular responses in mice. Moreover, the bacterial burden in the lungs was significantly lower in animals immunized with the NP-coated vaccine than in animals immunized either with the naked plasmid vaccine or with BCG. The use of fullerenols (Fig. 1i,j ) for the delivery of a HIV-1 Env-expressing plasmid DNA vaccine also led to improved T cell responses in mice, but this approach only marginally enhanced the humoral immune response 153 .

Our group has investigated fibrillar assemblies of short synthetic peptides, and while they have only begun to be explored in the context of the diseases of interest in this Review 154 , 155 , 156 , initial work has indicated that they possess a number of useful properties including considerable multivalency that allows them to raise strong T-cell and B-cell responses without requiring supplemental adjuvants 157 , 158 , synthetic definition and the ability to mix multiple epitopes or antigens. Several fibre-forming peptide systems have been reported including those based on β-sheet fibrillizing peptides such as Q11 or KFE8 91 , 95 , 159 , 160 , or α-helical fibrillar assemblies such as Coil29 161 . In each of these systems, peptide epitopes can be conjugated to fibrillizing assembly domains, which spontaneously self-assemble into defined nanofibres displaying the epitopes on their surfaces. Recent work has explored several facets of these materials, including surface properties necessary for maximizing or minimizing their immunogenicity 160 , applying them towards intranasal vaccination 159 , and applying them towards therapeutic vaccines countering inflammation 95 . To expand the capacity of fibrillar peptide assemblies to incorporate large, folded protein antigens, we have also developed strategies based on the capture enzyme cutinase 162 and designed expression tags termed β-tails 163 .

One of the challenges in developing vaccines towards malaria, HIV and TB is the global distribution of the diseases and their concentration in tropical and developing locations of the world. All current vaccines require uninterrupted maintenance between 4–8 °C, the so-called cold chain, adding additional practical challenges to the already daunting task of designing an effective vaccine. Peptide assemblies carrying peptide epitopes from the M. tuberculosis antigen ESAT-6 were strongly immunogenic even after storage at 45 °C for six months, indicating that this class of materials has advantageous thermal stability 154 . The repetitive malaria antigen (NANP) 3 from the falciparum circumsporozoite protein has also been found to be immunogenic on self-assembled β-sheet nanofibres 156 , and ESAT-6 has also been explored on nanofibres of the self-assembling peptide KFE8 155 . Collectively these studies indicate that fibrillar peptide assemblies are attractive platforms not only for enhancing vaccine immunogenicity but also for facilitating vaccine implementation in resource-limited areas.

Conclusion and outlook

There has been an explosion of nanomaterials explored as new vaccines. Coupled with parallel advances in antigen design, it is possible that multiple nanomaterial platforms may ultimately be capable of identifying and reliably raising the defined, engineered immune responses necessary for protection against HIV/AIDS, malaria or TB. Once appropriate immunogens are discovered, more than one platform may likewise offer increased thermal and environmental protection to enable distribution to the most resource-limited locations of the globe. A key question remaining, then, is how to efficiently sort through all of the different platforms and combinations of adjuvants, immunomodulating compounds, delivery considerations, dosing regimens and other factors that have been made available in recent years. In this endeavour, multifactorial Design of Experiment approaches may be particularly powerful. Additionally, benchmarking different platforms against each other during their development will have considerable advantages over more focused and self-referential investigations, as this will help clarify the relative strengths and weaknesses of specific platforms and materials. At present, some of the most valuable research outcomes achieved to date include the consolidation and articulation of concepts by which such materials raise useful immune responses. This basis of knowledge now supports the continued refinement of vaccines towards devastating global diseases. In parallel with advances in antigen design, we are optimistic that vaccines efficacious enough to significantly curtail the global impact of malaria, HIV and TB are within reach.

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Related research in our laboratories is currently supported by the NIH (NIBIB 5R01EB009701; NIAID 5R01AI145016), Duke MEDx, and the Duke Center for AIDS Research (CFAR). C.N.F. and E.J.C are supported by the National Science Foundation Graduate Research Fellowship Program (DGE-1644868). The content of this Review is solely the responsibility of the authors and do not necessarily represent the official views of these funding agencies.

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These authors contributed equally: Chelsea N. Fries, Elizabeth J. Curvino.

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Department of Biomedical Engineering, Duke University, Durham, NC, USA

Chelsea N. Fries, Elizabeth J. Curvino & Joel H. Collier

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA

Jui-Lin Chen, Sallie R. Permar & Genevieve G. Fouda

Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA

Department of Pediatrics, Duke University Medical Center, Durham, NC, USA

Sallie R. Permar & Genevieve G. Fouda

Department of Immunology, Duke University School of Medicine, Durham, NC, USA

Sallie R. Permar & Joel H. Collier

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Correspondence to Genevieve G. Fouda or Joel H. Collier .

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J.H.C., S.R.P., G.G.F. and C.N.F. are inventors on a patent application associated with the technology areas described.

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Fries, C.N., Curvino, E.J., Chen, JL. et al. Advances in nanomaterial vaccine strategies to address infectious diseases impacting global health. Nat. Nanotechnol. 16 , 1–14 (2021). https://doi.org/10.1038/s41565-020-0739-9

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Received : 04 July 2019

Accepted : 23 June 2020

Published : 17 August 2020

Issue Date : April 2021

DOI : https://doi.org/10.1038/s41565-020-0739-9

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Nanomaterials and Nanotechnology in Wastewater Treatment

The rapidly increasing population, depleting water resources, and climate change resulting in prolonged droughts and floods have rendered drinking water as a competitive resource in many parts of the world. Therefore, any form of water reuse or recycle will help to mitigate this challenge. The careful management of water and wastewater is a big challenge and the “hot” trend of recent research. During the past century, a huge amount of wastewater was discharged into rivers, lakes, and coastal areas. This resulted in serious pollution problems in the aqueous environment. Municipal, industrial, and natural activities produce large quantities of liquid wastes and effluents which pose severe threats to the environment and human health. So, it is mandatory to find the appropriate technique in order to efficiently treat and manage water and wastewaters. Some indicative/conventional methods are biological treatments, adsorption, flocculation, oxidation, membranes, filtration, etc. These conventional technologies focus only on the primary wastewater treatment, especially on the physical separation of solid particles and the release of high concentrations of toxic phosphorus, nitrogen, and other ionic compounds into the environment. Thus, the latest technology involving nanotechnology is highly potent in advancing wastewater treatment via nanomaterials (nanoadsorbents, nanocomposites, (photo)catalysts, nanofiltration, nanomembranes, nanoparticles, etc.). These nanomaterials have been established in the development of separation membranes, catalysts, and adsorbent materials to enhance the removal of specific components of wastewater and improve productivity. Zero-valent metal nanoparticles (Ag, Fe, and Zn), metal oxide nanoparticles (TiO 2 , ZnO, and iron oxides), carbon nanotubes (CNTs), nanocomposites, and many other types of nanomaterials are already used in wastewater treatment. All of the above can be achieved by using nanotechnology. This Special Issue on “Nanomaterials and Nanotechnology in Wastewater Treatment” seeks high-quality works and topics (not only those) focusing on the latest approaches based on nanotechnology to efficiently treat wastewater.

This Special Issue (belongs to the section Environmental Nanoscience and Nanotechnology) on “Nanomaterials and Nanotechnology in Wastewater Treatment”, we believe, succeeded to present such high-quality works and topics focusing on the latest novel nanotechnology works on wastewater processes. This Special Issue consists of 21 works (19 research articles, 1 review paper, and 1 communication) from distinguished authors worldwide [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ].

Khan et al. [ 7 ] evaluated the Fe–Mg binary oxide for As(III) adsorption in batch mode. Detailed synthesis, characterization and kinetic modeling were presented. Yadav et al. [ 19 ] studied the synthesis and characterization of methionine-functionalized graphene oxide/sodium alginate biopolymer nanocomposite hydrogel beads and their application as adsorbents for the removal of fluoroquinolone antibiotics (isotherms and kinetics were analyzed in detail). In another interesting work [ 5 ], authors investigated the CO 2 /CH 4 and He/N 2 separation properties and water permeability valuation of mixed matrix MWCNTs-based cellulose acetate flat sheet membranes in a study about the optimization of the filler material dispersion method. Zhu et al. [ 21 ] studied the adsorption kinetics of arsenic (V) on nanoscale zero-valent iron supported by activated carbon, while Ramos-Guivar et al. [ 13 ] focused on the improved removal capacity and equilibrium time of maghemite nanoparticles growth in zeolite type 5A for Pb (II) adsorption. In another “green” nanoadsorption study, Das et al. [ 3 ] investigated the green synthesis, characterization, and application of natural product coated magnetite nanoparticles for wastewater treatment (the effect of synthesized magnetic nanoparticles in wastewater treatment (bacterial portion), dye adsorption, toxic metal removal, as well as antibacterial, antioxidant, and cytotoxic activities were studied). Sekar et al. [ 14 ] published a work about the upcycling of wastewater via effective photocatalytic hydrogen production, using MnO 2 nanoparticles decorated activated carbon nanoflakes, while another study published by Mashentseva et al. [ 11 ] focused on Cu/CuO composite track-etched membranes for catalytic decomposition of nitrophenols and application to the removal of As(III). Yadav et al. [ 20 ] studied the synthesis and characterization of amorphous iron oxide nanoparticles by the sonochemical method and their application for the remediation of heavy metals (lead, chromium) from wastewater. Tao et al. [ 17 ] published the aerobic oil-phase cyclic magnetic adsorption to synthesize 1D Fe 2 O 3 @TiO 2 nanotube composites for enhanced visible-light photocatalytic degradation, while Ahmadi et al. [ 1 ] studied the acid dye removal from aqueous solution by using neodymium(III) oxide nanoadsorbents. Shu et al. [ 15 ] used almond shell-derived, biochar-supported, nano-zero-valent iron composite to remove Cr(VI) from aqueous solutions. Hasan et al. [ 6 ] synthesized in situ copolymerized polyacrylamide cellulose supported Fe 3 O 4 magnetic nanocomposites to adsorptively remove Pb(II), with special focus on artificial neural network modeling. On the other hand, Kumar et al. [ 16 ] studied the silver quantum dot decorated 2D-SnO 2 nanoflakes for photocatalytic degradation of the water pollutant Rhodamine B, while Xia et al. [ 18 ] investigated the removal of Hg(II) by EDTA-functionalized magnetic CoFe 2 O 4 @SiO 2 nanomaterial with core-shell structure. The enhanced kinetic removal of Ciprofloxacin onto metal–organic frameworks by sonication, process optimization and metal leaching study was published by Dehghan et al. [ 4 ], and Lee et al. [ 8 ] published the continuous flow removal of anionic dyes (Evans blue) in water by chitosan-functionalized iron oxide nanoparticles incorporated in a dextran gel column. Li et al. [ 9 ] investigated the synthesis of hierarchical porous carbon in molten salt and its application for methylene blue and methyl orange adsorption. Pruna et al. [ 12 ] tailored the performance of graphene aerogels for oil/organic solvent separation by one-step solvothermal approach, while Lin et al. [ 10 ] occupied with the preparation of CoMn 2 O 4 catalyst by using the sol–gel method for the activation of peroxymonosulfate and degradation of UV filter 2-phenylbenzimidazole-5-sulfonic acid. Also, a review article was published and included in the SI about the recent progress in heavy metal ion decontamination based on metal–organic frameworks [ 2 ].

Many authors, whom we, as editors, thank very much, from various countries contributed marvellously to the present Special Issue. All the aforementioned topics and many more were explored in detail. Certainly, the field of wastewater treatment using nanomaterials and generally nanotechnology is vast; the present study hopefully adds one more useful contribution.

Author Contributions

Writing—original draft preparation, A.C.M. and G.Z.K.; writing—review and editing, A.C.M. and G.Z.K.; supervision, A.C.M. and G.Z.K. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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How to grow inorganic functional nanomaterials—quantum dots—in the nucleus of live cells

by Science China Press

National Science Review recently published research on the synthesis of quantum dots (QDs) in the nucleus of live cells by Dr. Hu Yusi, Associate Professor Wang Zhi-Gang, and Professor Pang Dai-Wen from Nankai University.

During the study of QDs synthesis in mammalian cells , it was found that the treatment with glutathione (GSH) enhanced the cell's reducing capacity. The generated QDs were not uniformly distributed within the cell but concentrated in a specific area.

Through a series of experiments, it was confirmed that this area is indeed the cell nucleus . Dr. Hu said, "This is truly amazing, almost unbelievable."

Dr. Hu and his mentor Professor Pang attempted to elucidate the molecular mechanism of quantum dot synthesis in the cell nucleus. It was found that GSH plays a significant role. There is a GSH transport protein, Bcl-2, on the nucleus, which transports GSH into the nucleus in large quantities, enhancing the reducing ability within the nucleus, promoting the generation of Se precursors.

At the same time, GSH can also expose thiol groups on proteins, creating conditions for the generation of Cd precursors. The combination of these factors ultimately enables the abundant synthesis of quantum dots in the cell nucleus.

Professor Pang stated, "This is an exciting result; this work achieves the precise synthesis of QDs in live cells at the subcellular level. Research in the field of synthetic biology mostly focuses on live cell synthesis of organic molecules through reverse genetics.

"Rarely do we see the live cell synthesis of inorganic functional materials. Our study doesn't involve complex genetic modifications; it achieves the target synthesis of inorganic fluorescent nanomaterials in cellular organelles simply by regulating the content and distribution of GSH within the cell. This addresses the deficiency in synthetic biology for the synthesis of inorganic materials."

While the synthesis of organic materials in cells remains predominant in the field of biosynthesis, this research undoubtedly paves the way for the synthesis of inorganic materials in synthetic biology .

Professor Pang said, "Each of our advancements is a new starting point. We firmly believe that in the near future, we can use cell synthesis to produce nanodrugs, or even nanorobots in specified organelles. Moreover, we can transform cells into super cells, enabling them to do unimaginable things."

Provided by Science China Press

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