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A repertoire of biomedical applications of noble nanoparticles Mohammad Azharuddin, Geyunjian H. Zhu, Debapratim Das, Erdogan Ozgur, Lokman Uzun, Anthony P. F. Turner and Hirak Kumar Patra

The self-archived postprint version of this journal article is available at Linköping University Institutional Repository (DiVA): http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-158861

N.B.: When citing this work, cite the original publication. Azharuddin, M., Zhu, G. H., Das, D., Ozgur, E., Uzun, L., Turner, A. P. F., Patra, H. K., (2019), A repertoire of biomedical applications of noble metal nanoparticles, Chemical Communications, 55(49), 6964-6996. https://doi.org/10.1039/c9cc01741k

Original publication available at: https://doi.org/10.1039/c9cc01741k Copyright: ROYAL SOC Publisher URL Missing

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ARTICLE

A repertoire of biotechnological applications of noble metal nanocomposites

a b c d d Received 00th January 20xx, Mohammad Azharuddin , Geyunjian H. Zhu , Debapratim Das , Erdogan Ozgur , Lokman Uzun , Accepted 00th January 20xx Anthony P.F. Turner*e and Hirak K Patra*a,b,f

DOI: 10.1039/x0xx00000x Noble comprise any of several metallic chemical elements that are outstandingly resistant to and oxidation, even at elevated temperatures. This is not strictly defined, but the tentative list includes , , , , , , and , in order of atomic number. The emergence of noble metal nanotechnology is attracting huge interest from the scientific community and has led to an unprecendented expansion of research and exploration of applications in electrochemistry, catalysis and biomedicine. Noble metal nanocomposites can be synthesised both by top-down and bottom up approches, as well as via organism-assisted routes, and subsequently modified appropriately for the field of use. Nanoscale analogues of gold, silver, platinum, and palladium in particular, have gained primary importance owing to their excellent intrinsic properties and diversity of applications; they offer unique functional attributes, which are quite unlike the bulk material. Modulation of noble metal nanoparticles in terms of size, shape and surface functionalisation has endowed them with unusual capabilities and manupulation at the chemical level, which can lead to changes in their electrical, chemical, optical, spectral and other intrinsic properties. In this comprehensive review, we highlight recent advances in the adaptation of noble metal naomaterials and their applications in therapeutics, diagnostics, sensing, and environmental monitoring.

The antibacterial,8 antiseptic and anti-inflammatory activities of Introduction silver complexes have been reported worldwide.9–11 Another well studied noble metal-based drug is cisplatin (cis- Noble metals have a long and rich history which probably dates back diaminedichloroplatinum (II)), which represents one of the most to as early as the Egyptian First Dynasty. They belong to a class of potent chemotherapeutic agents against ovarian and testicular elements that has found a wide range of applications encompassing cancer.12,13 A vast library of metal complexes has been applied in the aerospace, electronic industries and most importantly, the health pharmacological field as anticancer, anti-inflammatory, antibacterial, 1–4 sector . The first use of gold dates back to the late 1800s, when it anti-rheumatic and anti-malarial drugs. The anti-tumour activity of was observed that low concentrations of potassium gold , these metal-based drugs can be attributed to their ability to undergo K[Au(CN)2] had antibacterial properties against tubercle bacillus. strong interactions with DNA, although there are other molecular Again, in the mid-1800s, gold therapy for tuberculosis and targets such as thiol-containing protein and redox processes. rheumatoid arthritis were introduced. More recently, Auranofin gold(I) complexes have made a tremendous positive contribution to The amalgamation of nanoscience and biotechnology has spawned a 5–7 the treatment of cancer and malaria. Likewise, it is a well-known growing field of research in the form of nanobiotechnology. In this that most bacteria are affected adversely by silver. Since the late new arena, the technological leap of synthesising and controlling 1800s, silver nitrate solutions have been employed as topical eye materials at nanoscale level has provided an immense opportunity to drops for curing blindness because of their anti-microbial property. progress medical and healthcare treatment, diagnostics and therapies.14 Noble metals are eclectic non-toxic agents in the sense that they have a wide diversity of biomedical applications, which a. Department of Clinical and Experimental Medicine, Linkoping University, include use in highly sensitive diagnostic assays,15 thermal ablation Linkoping, Sweden 16–19 b. Department of Chemical Engineering and Biotechnology, University of Cambridge, as radiotherapy enhancers, and drug and gene delivery Cambridge, UK vehicles.20–26 Nanoparticles based systems are now becoming an c. Department of Chemistry, Indian Institute of Technology Guwahati, India effective tool in “Theranostics” (i.e. simultaneous diagnosis and d. Hacettepe University, Faculty of Science, Department of Chemistry, Ankara, therapy) because of their unique property of excellent penetration Turkey. e. SATM, Cranfield University, Bedfordshire, MK430AL, UK and tracking within the body, which allows for a more efficient f. Wolfson College, University of Cambridge, Cambridge, UK therapy with a reduced risk of any toxic side effects in comparison to conventional therapies.2724,28,29 The unique characteristics of noble † Footnotes relating to the title and/or authors should appear here. metal nanostructure, in terms of high surface-to-volume ratio, broad Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 10.1039/x0xx00000x optical properties, ease of synthesis, and tunability of surface functionalisation and modification provide an important dimension

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ARTICLE Journal Name in bio-diagnostics, biophysical studies, biosensing and medical Top-down approaches therapy.24,28,29 One of the commonly used protocols is micropatterning.51 Apart Noble metal nanomaterials have played an equally important role in from the most common approach of photolithography, various other the development of novel biosensors, which adds to or enhances the techniques have evolved in the recent past.52 Scanning, soft, nano- accuracy and specificity of already existing repertoire of imprint, colloidal, nanosphere and E-beam lithography are among biomolecular diagnostics. The physicochemical attributes of noble some of these new methods. In principle, all these techniques use metals at the nanoscale level have led to the development of a wide either light, electrons, a focused beam of electrons or electrostatic variety of biosensors such as: (i) nanobiosensors for point care forces to selectively remove nano-structures from a precursor to disease detection, (ii) nanoprobes for in vivo cell imaging, tracking develop ordered arrays of nano-materials. and pathogenesis of disease progression and (iii) other nanobiotechnology-based tools that enhance basic biological In a milling process, macro-scale materials are ground in a ball mill to research.30–33 generate particles of nano dimensions.53 The kinetic energy transfer from balls to powder is behind the reduction in grain size. Various The colloidal state of noble metals has been the subjects of intensive parameters like, type of mill, milling atmosphere, milling media, investigations because of their effectiveness and various questions intensity, time, temperature, etc. play a crucial role in controlling the have been raised regarding their safety profile in human body. shape and size of the nanoparticles.54 Different devices designed for Colloidal gold, silver, platinum, palladium, iridium, ruthenium and various purposes have been developed in order to overcome these rhodium are easily and widely available on the market for use in constrains including shaker mills, tumbler mills, vibratory mills, combating many diseases, free radicals and bacteria. In this review, attrition mills, planetary mills, etc. For bulk production of nano- we provide an extensive literature survey covering recent materials, the attrition process is highly advantageous. However, one developments in this field. major limitation of this process is the imperfect surface and significant crystallographic damage of the processed materials. Pyrolysis is another important technique commonly used.55 A Synthetic Routes for Noble Metal Nanoparticles precursor in its vapour state is forced through an orifice with high The preparation of nanoparticles fundamentally follows two pressure and burning. Through further processing of the obtained distinctly different approaches, top-down and bottom-up (Scheme solid ash, nanoparticles are recovered. Pyrolysis is frequently used 35,56 1).34 The top-down processes involve bulk materials which are for the preparation of noble metal nanoparticles. One important reduced to particles with nano-dimension using various physical and drawback of the method is the requirement for large amounts of chemical methodologies. On the other hand, in a bottom-up energy. approach, nanoparticles are constructed through the assembly of the atoms, the molecules, or the clusters and thus this is generically termed self-assembly. Bottom-Up approaches

Externally controlled tools are utilised in a top-down approach for cutting, milling and shaping the materials into the desired order and The most commonly utilised and easiest bottom-up approach is the shape. Several physical methods, such as pyrolysis,35 lithography,36– chemical reduction of metal ions in solutions. In principle, an ionic 38 thermolysis,39,40 and radiation-induced methods41 belong in this salt is reduced using various reducing agents under appropriate 43–45 category. A major limitation of the top-down approach is the reaction conditions and in presence of a stabilising agent. A imperfect surface structure of metallic nanoparticles, which plethora of reducing agents, such as Na-citrate, hydrazine, hydrogen, substantially affects their physical and chemical properties.42 LiAlH4, NaBH4, and alcohols can be used. According to Lee-Meisel 57 Moreover, enormous energy is required to maintain the high method, nitrate and sulphate salts are reduced using NaBH4, pressure and high-temperature conditions during these synthetic sodium citrate, and hydrogen. The pH of the medium plays a crucial 58 procedures and this makes these processes expensive. role in modulating the size and shape of the particles. At high pH, owing to faster reduction, both rod and spherical nanoparticles were In a bottom-up methodology, the originally formed nanoparticles are found, while at relatively lower pH (5-6), triangular and other subsequently assembled into the final material, using chemical as polyhedral structures were obtained because of the slower reaction. well as biological procedures. The bottom-up approach is Similarly, Au nanoparticles can be prepared from an aqueous 59,60 advantageous as it provides a far better control over the final product solution of HAuCl4 using citrate as the reducing agent. The formation with less surface deformation and more homogeneous average particle size can be controlled by varying the ratio of chemical composition. Moreover, the processes are in general less reducing/stabilising agents as well as the pH of the system.61,62 On expensive as well. The bottom-up approach is commonly used for the other hand, platinum, another important class of noble metal wet synthesis procedures, such as chemical,43–45 electrochemical,46,47 nanoparticle is relatively under explored. Sodium polyacrylate polyol reduction48 and sonochemical.49,50 However, one major stabilised cubic and tetrahedral platinum nanoparticle synthesis in drawback of these processes is the use of toxic chemicals, organic solution phase has been reported by El-Sayed et al.63 A general solvents and reagents. strategy based on a chemical reduction method involving different metal combinations (cobalt, iron, and nickel) with platinum has been reported by Zhang.64 Another popular nanoparticle fabrication process involves microemulsions. The first microemulsion-based synthesis was reported for palladium, rhodium, and platinum nanoparticles synthesis.65 Since then, the process gained popularity owing to its ease of operation and control over the size and shape of

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Journal Name ARTICLE the products.66–68 Herein, two separate microemulsions containing Considering the excess use of chemicals and solvents in the chemical salts and reducing agents are mixed together in presence of synthesis of nanoparticles, greener approaches with minimal use of amphiphile. Inter microemulsion collision leads to the mixing of the such hazardous chemicals have been developed. One major driving reactants and consequently nanoparticles are formed. This strategy force for these greener approaches is nature’s efficiency in making helps in growing nanoparticles with uniform shape and size as the these nano-materials. Mimicking nature, may not be not easy, but it microemulsions are used as a template while the nanoparticles are has allowed to develop several green synthetic protocols growing during the process. This method offers benefits to prepare for nanoparticle synthesis using water as the medium and proteins thermodynamically stable and monodispersed nanoparticles.69 or carbohydrates as capping agents.79,80 Starch has been used as both a reducing as well as a stabilising agent for the synthesis of stable silver nanoparticles.81,82 Similarly, gold nanoparticles have been prepared utilising different biomolecules as capping agents and lactic acid as the reducing agent.82 Chitosan, a natural biopolymer, has also been used as a reducing and stabilising agent.83 In another “greener” approach, hydrogels of synthesised peptides and other small molecules were successfully used to create nanoparticles where the hydrogel nano-structures act as the template and help in creating the shape and size of the nanoparticles.84,85 Das et al. prepared a tryptophan-appended peptide amphiphile able to form hydrogel where gold nanoparticles with defined shape and size could be prepared using the indole residue as the reducing agent, without the need for any external agent.86,87

Organism-based synthesis of nanoparticles

The quest for the development of economically as well as environmentally benign methods led to exploration of the potential of micro-organisms in this respect.88 Biological systems are excellent examples of hierarchical organisations of atoms or molecules and Scheme 1 Schematic presentation of the top-down and bottom-up approaches for this attracted researchers to use micro-organisms as potential cell nanoparticle synthesis. factories for nano-material preparation. Both prokaryotic (bacteria) and eukaryotic (algae, fungi, plants) species are used for this purpose. In a laser ablation process, a solid surface is irradiated with a laser beam and the materials become heated at low laser flux and are finally evaporated or sublimated.70 At a higher flux, the materials are Bacteria are often exposed to metal rich environments and have the converted to form plasma. The lack of any requirement to remove ability to develop resistance to these extreme conditions. Thus, excess reagents as well as the possibility of metal nanoparticle prokaryotes like bacteria are an automatic choice for the production synthesis in both aqueous and organic solvents has allowed the laser of nanomaterials. Pseudomonas stutzeri AG259, a metal ablation method to emerge as a potential alternative for chemical accumulating bacterium, was utilised by Klaus et al. to create reduction methods. There have been several reports where this intracellular nanocrystals of metallic silver and monoclinic silver 89 process was used to prepare a variety of noble metal nanoparticles sulphide. Extracellular synthesis of nanoparticles was first reported 90 including silver, gold, and platinum.71–73 Fast processing times, by Shahverdi and co-workers. Nanocrystals of silver were prepared control over the size and shape of the particles and high yields are by incubating the biomass of Bacillus licheniformis in presence of among the major advantages of this process. silver nitrate, where NADH acted as the reducing agent in presence of nitrate reductase.91 Gold nanoparticles are also prepared by accumulation and reduction of gold salts by bacteria. Bacillus Microwave-based synthesis and electrochemical methods are the licheniformis, Shewanella algae, Stenotrophomonas maltophilia, other two important approaches to be mentioned. Microwave Lactobacillus strains, present in the whey of butter milk are some of irradiation is used for the “one-pot” preparation of metal the examples of bacteria which have been used to produce gold nanoparticles from their salts and polymeric surfactant solutions.74 It nanomaterials.92–95 In addition to these, bacteria like Schewanella is a relatively fast and easy method with high selectivity and control and Acinetobactor calcoaceticus PUCM 1011 were utilised for the over size and morphology of the end products.75 The electrochemical preparation of platinum nanoparticles.96,97 method was first introduced by Reetz.76 A metal sheet was dissolved from the anode and the metal salt thus produced was reduced on the cathode of an electrochemical cell producing the desired metal Though promising in terms of its green nature and control over the nanoparticles.77,78 Importantly, control over the particle size can shape and size of the particles, bacterial-mediated synthesis suffers easily be achieved without any template. from disadvantages such as difficulty in handling and low yield. In recent years, eukaryotic organisms have emerged as a better alternative for the synthesis of noble metal nanoparticles, owing to easier protocols as well as cost-effectiveness. Fungi were first tested

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ARTICLE Journal Name by Sastry et al. for the preparation of metal and metal nanoparticles.98 Gold nanoparticles were prepared using Verticillium sp. when AuCl4 was reduced within the fungal cells. Fusarium oxysporum was used to prepare gold and silver nanoparticles with uniform dimensions.99 An environmentally friendly and cost- effective method for the synthesis of silver nanoparticles using cell- free filtrate of Aspergillus flavus was reported by Panwar and coworkers.88 Another important biological media are the algae. Algae, like Chlorella vulgaris and Pithophora oedogonia, have been used successfully to construct silver nanoparticles.100,101 Gold nanoparticles have been prepared involving various seaweeds like

Sargassum wightii by Singaravelu et al.102 Plant extracts are also attractive media for the synthesis of nanoparticles and the process Fig. 1 Schematic illustration of representative anchor moieties, stabilizing spacers, has been referred to as Phytosynthesis. Live alfalfa plant can take tethering groups, and conjugation groups for functionalising noble nanoparticles. NHC = gold ions from solid media and the secretome from live alfalfa plant N-heterocyclic carbenes, NHS = N-Hydroxysuccinimide, EDC = 1-ethyl-3-(3- can reduce gold ions to Au0, which can be taken up by the plant and dimethylaminopropyl)carbodiimide hydrochloride. consequently used to produce gold nanoparticles.103 Neem (Azadirachta indica) leaf extract was successfully used by Shankar et al. to prepare silver, gold, and bimetallic Au/Ag core–shell Characterisation of Noble Metal Nanoparticles nanoparticles.104 Similar plant extracts (bark, leaf, fruit, and gum) have been used by several researchers to produce a variety of noble metal nanoparticles.105–108 The unique properties of noble metal NPs such as thermal, electrical, chemical, and optical rely on the size, morphology and surface As discussed, several physical, chemical as well as biological methods charge. Various techniques have been developed to characterise the have been developed for the synthesis of nanoparticles. All these metal NPs.122 Size distribution, average particle diameter, surface processes are widely used based on the utility and applicability of the charge, and shape govern the physical stability of metal NPs.123 nano-products. However, the existing protocols all suffer from Scanning electron microscopy (SEM),124 dark-field and field-emission certain drawbacks. Thus, the development of alternate processes to scanning electron microscopy (FE-SEM),125,126 transmission electron fabricate nanoparticles with controlled and tuneable properties is microscopy (TEM),127 high-resolution TEM (HRTEM),128–130 and still an open challenge. atomic force microscopy (AFM)131,132 are commonly utilised to estimate the size, shape, and surface morphology. Dynamic light scattering (DLS) observations enable the determination of particle sizes and their size distributions in situ.133,134 Small-angle X-ray Surface Modification and Functionalisation of scattering (SAXS), extended X-ray absorption fine structure (EXAFS), Noble Metal Nanoparticles X-ray absorption near-edge structure analysis (XANES), and electron spin resonance (ESR) provide information about the local structure Nobel metal NPs have attracted significant attention in various and electronic properties of metal NPs with different surface applications ranging from electronics to sensing, biolabeling, chemistry and morphology.135,136 X-ray photoelectron spectroscopy photonics, nanomedicine and catalysis, due to their electrical, (XPS),137 Fourier transform infrared (FTIR) spectroscopy and solid- chemical, optical, spectral and other intrinsic properties.109,110,111 To state nuclear magnetic resonance spectroscopy (SSNMR) can be increase the biocompatibility, sensing, and specific targeting of NPs, used to obtain information about surface chemistry of metal NPs.138 it is necessary to stabilise NPs against agglomeration and to Matrix-assisted laser-desorption ionisation time-of-flight (MALDI- functionalise them.112–114 Attaching appropriate organic groups to TOF) mass spectrometry (MS), inductively coupled plasma mass the metal surfaces is the most common way to achieve this (Fig. 1). spectrometry (ICP-MS), UV−vis spectroscopy and exclusion Through metal−thiolate (M−S) linkages,115 organosulphur groups chromatography with UV−vis detection (SEC-UV−vis) have also all coordinate to various metals such as Ag, Cu, Fe, Au.116 Metal−carbon been utilised to characterise various properties of nanomaterials (M-C=) covalent bonds using aryl diazonium as the precursors117 have (Fig. 2).122,139,140 Energy-Dispersive X-ray spectroscopy (EDX) analysis been used to stabilise metal NPs. Metal−carbene (M=C) or can be used to confirm the chemical composition of the metal NPs.127 metal−nitrene (M=N) π bonds formed with diazo derivatives, have been utilised to functionalise various metal NPs such as Au, Pt, Ti, Ru, and Pd.118,119 Metal−acetylide/−vinylidene bonds are formed via acetylene derivatives onto metal surfaces.120 Surface modification or functionalisation of metal NPs can be accomplished with amines or ammonium ions, negatively charged carboxylate groups, and phosphines.121

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uptake of noble metal nanoparticles. It has been reported that 40-50 nm particles have the most effective cellular internalisation.146,147 In a separate study, it was shown that 50 nm GNPs can enter into cells at a relatively faster rate and at a higher concentration than other sizes.145 This observation was further validated by both in vitro and in vivo studies.148 AsPC-1, PANC-1, and MiaPaca-2 (pancreatic cell lines) upon incubation with GNPs of varying hydrodynamic radii, exhibited the greatest uptake for 20 nm particles, as shown by TEM analysis. Another important factor which modulates cellular internalisation of noble metal nanoparticles is surface charge.149,150 The exterior of the cell is mostly anionic; hence positively charged noble metal nanoparticles can easily traverse through the cell membrane via electrostatic interaction.149 However, negatively charged noble metal nanoparticles have also been observed in the cell interior as a result of them passively targeting lipophilic domains.151 One report suggests that zwitterionic noble metal nanoparticles can be a potent and highly efficient drug delivery system.152,153

Fig. 2 Evolution of optical absorption spectra of gold clusters with various sizes, measured at different temperatures, as indicated. Au n clusters with n = 38, 130 and 144 show discrete energy states in the spectra and have icosahedral (I) or Marks decahedral (M-Dh) structures, whereas the clusters with n = 187, 226, 329 and 520 have plasmonic resonances originating from their metallic band structure and a face-centred ∼ ∼ cubic (fcc) structure. Reprinted with permission from Reference (10.1038/natrevmats.2016.34)

Therapeutic Relevance of Noble Metal Nanoparticles

Complexes of noble metals have been used as therapeutic agents since ancient times. With the advent of nanobiotechnology, there has been a surge towards the development of different kinds of nanostructures with a diverse range of biomedical applications (Fig. 3). In this regard, noble metal nanomaterials have gained primary importance; there are several reasons for this including: (i) ease of Fig. 3 Biomedical applications of nanoparticles through conjugation with various active size and shape modulation; (ii) unique optical and photothermal moieties including nucleic acids, peptides, receptors, antibodies, and small molecules. properties; and (iii) surface functionalisation. Since these nanomaterials can interact with biomolecules both at the surface Angiogenesis has been shown to be critically involved in a number of and inside the cell, they represent an excellent repertoire of diseases such as cancer, rheumatoid arthritis, and macular biocompatible nanoscale drugs. These noble metal nanoparticles can degeneration.154,155 Under normal conditions, angiogenesis is tightly be synthesised both chemically and biogenically with high regulated by various anti-angiogenic factors such as efficiency,141,142 and these engineered nanoscale versions of noble thrombospondins (TSP-1), platelet factor 4, vascular endothelial metals have inspired researchers to develop innumerable growth factor (VEGF), platelet-derived growth factor (PDGF), and therapeutic agents for the treatment of a wide range of transforming growth factor beta (TGF-β).156 Under pathological diseases,143,144 where nanotechnology-based approaches have been condition, this balance is disrupted and this leads to angiogenesis.156 shown that play a significant role in treatment and early diagnosis of In such cases, there is generation of highly abnormal blood vessels, these diseases. This section will point out some of the unique which become hyperpermeable to plasma proteins. therapeutic abilities of noble metal nanostructures. A number of anti-angiogenic agents have been clinically tested but they seem to target only the VEGF157 mediated signalling.158 Also, The uptake of inorganic or noble metal nanoparticles has been these agents possess serious toxicities which result in hypertension, studied extensively in recent years. The mechanism of cellular thrombosis, and fatal hemorrhage.154,155 Here, noble metal internalisation of noble metal nanoparticles such as gold, silver and nanoparticles can be used as an effective anti-angiogenic agent, platinum are not necessarily similar and are, at the same time, since they have the ability to target multiple pathways involved in ambiguous. Size, shape, surface charge, and surface chemistry play angiogenesis.159 Uncapped GNPs exhibit anti-angiogenic properties extremely important roles in cellular uptake both in vitro and in vivo. by inhibiting the activity of heparin-binding proteins such as VEGF157 Spherical gold nanoparticles (GNPs) exhibit greater cellular uptake and basic fibroblast growth factor (bFGF) in vitro and VEGF induced than their corresponding rod structures.145 Also, size determines the angiogenesis in vivo.160 It was observed that heparin-binding proteins

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ARTICLE Journal Name are absorbed on the surface of the GNPs and lose their functional been deployed as photothermal therapy (PTT) agents against A431 attributes.161 The size of GNPs also dictates their anti-angiogenic cells. This study showed that upon exposure to low levels of laser activity; in one study it was shown that VEGF157 preincubated with light, GNPs induce the destruction of the malignant cells through GNPs of varying size (5-20 nm) had a dramatic effect on VEGF reactive oxygen species (ROS) mediated apoptosis (Fig. 4a).176 signalling events.162 The suppression of heparin-binding growth Further, the shape of the GNPs plays an extremely important role in factors by nanoparticles has further explained their effectiveness PDT therapy, GNPs with different geometry were tested against against multiple myeloma via inhibiting VEGF- and bFGF- dependent HUVEC cells and it was noted that gold nanorods were 100 times proliferation as tested in cell lines OPM-1, RPMI-8266, and U-266. more potent than the other shapes tested.177 Similarly, mice injected This study revealed that cells are arrested in the G1 phase of the cell with GNPs had a significant reduction of deep tissue tumours after a cycle with an up-regulation of p21 and p27.163 The anti-angiogenic brief exposure to NIR.178 GNPs have been used for treatment of skin properties of GNPs could also modulate the status of B-chronic cancer; GNPs were administered into the tail vein of mice and local lymphocytic leukemia (B-CLL) cells.160 Exposure of GNPs to B-CLL cells laser induced hyperthermia was employed for reduction and resulted in an increase in apoptosis in a dose-dependent manner.164 complete inhibition of skin tumours.179 Radio frequency ablation Angiogenesis also plays a crucial role in the promotion and (RFA) in conjunction with GNPs has proved to be an effective maintenance of inflammatory diseases such as rheumatoid arthritis treatment strategy for liver cancer cell (HepG2) lines; here citrate (RA). It has been observed that 13 nm GNPs exhibit anti-rheumatoid coated GNPs demonstrated a time-dependent cytotoxic effect upon activity in collagen-induced arthritis in rats.165 GNPs bind to VEGF in exposure to the RF field.180 Noble metal nanoparticles offer an the synovial fluid of patients suffering from RA and affect their attractive advantage in radiotherapy owing to their excellent optical cellular proliferation and migration. Further, histological studies properties, surface plasmon resonance, and surface modalities. For showed that there is reduction in tumour necrosis factor alpha (TNF- example, upon X-ray irradiation, GNPs have been shown to induce α) and interleukin beta (IL-β) after intra-articular administration of cellular apoptosis by the generation of ROS.181 This therapeutic GNPs. Silver nanoparticles (AgNPs) have also been shown to act as an treatment strategy has effectively increased the percentage of anti-angiogenic agent. AgNPs with size of 40 nm were used to study cancer cells killed without harming the nearby surrounding healthy their anti-angiogenic properties in bovine retinal epithelial cells tissue.182,183 Mice injected with GNPs upon X-ray exposure exhibit a (BREC). AgNPs successfully inhibited cell proliferation and migration fourfold reduction in tumour size and also an extended lifetime of in VEGF induced angiogenesis in BRECs and prevented the formation the animal.184 of new blood vessels.164 Furthermore, tumour bearing mice demonstrated a reduction of ascite production and suppression of tumour progression upon treatment with AgNPs.166,167

Cancer is one of the largest life-threatening diseases worldwide and has led to millions of deaths, most of them in developing countries. A combination of surgery, chemotherapy and radiation therapy constitutes the major treatment procedures for almost all cancer Fig. 4 (a) Schematic representation of ROS generated tumour cell death using NIR therapy. Since these conventional therapeutic regimens are whole induced metal nanoparticles (b) TEM images of Au nanocages for which the surface was body approach, there is significant systemic damage to healthy covered by a pNIPAAm-co-pAAm copolymer with an LSCT at 39oC. The inset shows a 159 tissues and subsequently health-related issues. In order to magnified TEM image of the corner of such a nanocage. (c) Schematic illustration of the minimise the damage to non-cancerous tissue, noble metal controlled-release system (cross-sectional view): upon exposure to a near-infrared laser, nanoparticles have been utilised as a potential cancer therapeutic the light is absorbed by the nanocage and converted into heat, leading to the collapse of agent for non-invasive tumour treatment.168 In this regard, smart and release off loaded drugs. application of a magnetic field selectively heats the nanomaterials, which allows for selective and effective destruction of tumour Transport of drugs or therapeutic agents into the cells by GNPs have cells.168 Currently, photodynamic therapy (PDT), regional been the subject of intensive studies in biomedical treatment. hyperthermia, and radiotherapy are actively being exploited for Surface functionalised gold colloids have been extensively studied localised cancer treatment.109,169,170 PDT treatment is mainly for interaction with the cell membrane for efficient and improved achieved by focusing the light source on the affected area of the drug delivery.150,185,186 In one report, it was observed that surface body. The spectrum of light used here is in the range of 630-900 nm, ligand rearrangement on GNPs can regulate cell membrane that is the near infrared region (NIR), which is readily absorbed by permeability.151 Gold nanoparticles functionalised with an ordered the tissue.169 This range of wavelength minimises the light extinction arrangement of amphiphilic molecules were able to penetrate the by intrinsic chromophores in the normal or healthy tissue.171 In cell membrane more efficiently than particles with a disordered regional hyperthermia tumour therapy, the cancerous cells are arrangement of the same molecules that were entrapped in vesicular damaged upon exposure to elevated temperatures.172 There is loss bodies. The therapeutic activity of GNPs on cells can be regulated of membrane integrity, DNA damage, and induction of apoptosis as through passive and active targeting mechanisms. Passive targeting well as necrosis within a few hours.173 In radiation therapy, cancer is based on the concept of an enhanced permeability and retention patients are treated with ionising radiations, which is effective but at (EPR) effect; here gold colloids can extravasate into the tumour the same time it is invasive with numerous side effects on healthy stroma because of the defective vasculature and increased lymphatic tissues. Noble metal nanoparticles hold great promise as PDT, drainage leading to its accumulation at the target site (Fig. 5).159,187 hyperthermia, and radiotherapy agents. Surface plasmon resonance Active targeting relies on surface tuneability of GNPs specifically (SPR) of noble metal nanoparticles has been effectively exploited for designed for the target molecules to provide high specificity and PDT anticancer treatment.174 In one study, it has been shown that selectivity.188–190 These attributes of gold nanostructures have been GNPs can act as PDT agents and selectively destroy cancerous cells developed for applications in photothermal therapy,191–193 genetic at very low laser frequency.175 Citrate capped GNPs (15 nm) have also regulation,194–196 and drug treatment.197,198 GNPs are considered a

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Journal Name ARTICLE potential and powerful therapeutic probe for specific and selective Fig. 5 (a) Schematic illustration of tumour microenvironment. (b) Mother vessels with killing of cancer cells.199 GNPs scaffolds have been synthesised for thinned or compressed endothelial cells, degraded basement membranes, and pericyte detachment are highly permeable to both small molecules and proteins. Mother vessels use as transfection agents in gene therapy for curing cancer and can further differentiate into glomeruloid microvascular proliferations, vascular genetic disorders. GNPs coated with oligonucleotides are being malformations, and capillaries. (c) Schematic representation of transcellular and applied as intracellular gene alteration agents for controlling protein intercellular transport of nanoparticles from across vessel wall. expression in cells.200 Ribonucleic acid (RNA) modulated colloidal gold nanoparticles have been successfully tested for knockdown of A few GNP products have been approved for use in clinical luciferase activity,201 because the conjugated nanomaterials possess applications; these nanodrugs harness the light-absorbing ability of an extended half-life as compared to double-stranded(ds)-RNA, GNPs and are being currently explored for treating solid tumours and demonstrating a high gene knockdown capability in cell models. acne. One such gold colloid nanodrug approved for clinical trials is Positively charged amino acid coated GNPs have proved to be AuroLase, developed by Nanospectra, this comprises silica-gold effective and non-toxic transfection vectors for DNA delivery, nanoshells coated with polyethylene glycol (PEG) designed for the providing up to 28 times greater effectiveness than the conventional treatment of solid tumours by thermal ablation using a NIR source.209 negatively charged polylysine version.202 Here, silica provides a dielectric core, gold nanoshells confer thermal ablation ability, while the PEG induces an overall stability to the Targeted delivery of drugs has been carried out efficiently using gold nanocomposite.19 In another example, Sebashells developed by colloids by loading drugs onto GNPs through non-covalent or Sebacia Inc., which are similar to AuroLase, have been applied to covalent interactions. Drug entrapment with GNPs is achieved treat acne by disrupting overactive sebaceous glands in the skin.210 through the use of hydrophobic or hydrophilic pockets203 presented These Sebashells are topically administered to the site of acne, by the monolayer. Polymer encapsulated GNPs provide an delivered deep into the sebaceous glands by low frequency amphiphilic surrounding for the entrapment of hydrophobic silicon ultrasound and ultimately stimulated via a NIR laser, utilising the phthalocyanine 4 (Pc 4), a photodynamic therapy (PDT) agent.204 This heating capacity of the gold nanoshells for effective acne treatment conjugation releases the drug efficiently and quickly and deep into (Fig. 4 b and c). These studies have been done in vivo showing the tumour tissues within hours of incubation. Covalently conjugated potential efficacy of Sebashells in preventing inflammatory acne GNPs drugs are released through glutathione (GSH) displacement205 lesions.209 or through linker cleavage.206 A GSH-mediated release strategy using 6-mercaptopurine-9-b-D-ribofuranoside functionalised GNPs, has Silver nanoparticles (AgNPs) possess anticancer and antitumour been used to enhance anti-proliferative activity against K-562 cell properties by inhibiting angiogenesis around tumour tissues. This has lines compared to the free drug.207 The GSH-mediated pathway has led to an extensive research regarding the potential application of also been investigated to track the movement of GNPs carrying AgNPs in cancer treatment both in vitro and in vivo. These studies either fluorescein or doxorubicin molecules into a tumour model.208 have been conducted on different cancerous cell line models such as MCF-7, B10F17, A549, SiHa, and HeLa cell lines. Monomeric polymer encapsulated AgNPs have shown antileukemic properties against AML human cell lines.211 This study provides a dose and size dependent response of AgNPs against these cell lines in vitro. AgNPs proved to be a potent antileukemic agent by providing high specificity against AML cell lines as opposed to normal hematopoietic cells. The mechanism behind this activity is that AgNPs increase the production of ROS and release of silver ions (Ag) from nanomaterials, this results in the induction of apoptosis and DNA damage. The release of Ag ions from AgNPs has also been proposed to induce tumour cell sensitisation,212 these Ag ions are captured by free electrons, generating an oxidising agent which reduces the production of ATP in tumour cells and subsequently enhances intracellular ROS concentration. It has also been reported that release of Ag ions from AgNPs is greater as compared to bulk or powder silver.213 Silver ions do not produce hydroxyl radicals (•OH) in the presence of H2O2, which is a mild reducing agent. In contrast, AgNPs produce •OH in the presence of H2O2 only at acidic . This pH dependent •OH production by AgNPs confers their anticancer and antitumour activity. Biogenically synthesised AgNPS have also shown anticancer properties,214 like AgNPs synthesised from mushroom which were tested against MDA-MB-231 human breast cancer cell lines. AgNPs disrupt the cell membrane integrity and increase production of lactate dehydrogenase (LDH), a biomarker for cell death. AgNPs synthesised using Bacillus funiculus and leaf extract from Podophyllum hexandrum, causes caspase mediated apoptotic cell death.215,216 The antitumour activity of AgNPs was studied in multiple drug resistant (MDR) malignant melanoma cell tumours in vivo.217 Here, transactivator of transcription (TAT) was anchored onto AgNPs surface; this conjugation increases the antitumour activity by several fold.

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Cisplatin, a platinum complex, has been used for several decades for photostability than even gold and silver nanostructures. When treating a number of abnormalities. In contrast, the application of palladium nanosheets are coated with GSH, they demonstrate better platinum nanoparticles (PtNPs) as therapeutic agents is still in its renal clearance.236 In vivo studies have shown that in the absence of infancy.218 PtNPs possess the penetration capacity of entering cells219 any irradiation, these GSH-palladium nanosheets exhibited longer and the uptake and bioactivity of PtNPs have been investigated retention time in the circulating blood, accumulate near the tumour thoroughly which includes their cytotoxicity, genotoxicity, and site, and showed no toxicity, whereas upon irradiation with NIR laser, effects on protein expression in human cells.219 PtNPs penetrate into tumour ablation occurs.236 The attractive properties of these the cells through diffusion and are localised inside the cytoplasm. nanostructured materials have further extended their application in Upon exposure to PtNPs several events take place inside the cells more complex assemblies for combined photothermal- such as, DNA damage at the S-phase of the cell cycle ultimately chemo/photothermal-photodynamic therapy treatment. Anti- leading to apoptosis, up regulation of p53 and p21, and down cancer drug loaded silica nanoparticles entrapped within palladium regulation of proliferating cell nuclear antigens. These intracellular nanosheets have proved to be an effective treatment strategy for effects of PtNPs make it a potent anticancer therapeutic candidate combined photothermal and chemo-therapy; heat resulting from the for future use. In vitro PtNP treatment elicits DNA damage and NIR light conversion leads to pH dependent release of anti-cancer antioxidant response.147 The anti-cancer activity of platinum drugs and the cellular uptake of palladium nanosheets was nanomaterials220 has been shown in a recent study where significantly enhanced by the mesoporous coating of the silica synchronous application of PtNPs in conjunction with hadron nanoparticles.237 therapy resulted in enhanced DNA strand disruption. Irradiation of platinum by carbon ion leads to the generation of •OH radicals which Antimicrobial Activities of Noble Metal 221 in turn amplifies the extent of damage to DNA. An investigation Nanoparticles with human colon carcinoma cells (HT29) exhibited a size-, dose-, and time-dependent response upon incubation with PtNPs.147 The Concern regarding growing microbial resistance to all types of mechanistic reason behind the DNA damage was due to the release antimicrobial agents used against different infectious diseases has of Pt2+ ions from PtNPs causing a significant DNA damage and cellular led to a fusion between nanotechnology and microbiology. Broad- apoptosis.219,222 Hence, it was predicted that the nanoparticle itself spectrum activities of noble metal nanostructures and their does not interact directly with DNA, instead the soluble Pt2+ ions application to resolve microbial resistance issues have initiated a form a complex with DNA similar to cisplatin.219 Culturing cells with positive development in this field. The antibacterial, antifungal, PtNPs leads to the subsequent activation of p53 and p21, which antiviral, and antiprotozoal property of noble metal nanoparticles causes genotoxic stress.222 Thus, PtNPs can be potentially used in have attracted huge interest from the scientific community radiosensitisation as well.220 throughout the world (Fig. 6). This section will elucidate some of these diversified and multifunctional facets of noble metal Well documented studies on metal nanodrugs such as gold, silver nanoparticles with regards to their antimicrobial potentials (Table 2). and platinum have been thoroughly carried out for an extended Apart from their roles as antitumour agents, GNPs have been of time and some of them have even found their way into employed to deliver antibiotics and antibacterial agents as well. A clinical trials (Table 1).5 Technologies based on alternative noble variety of antibiotic conjugated gold colloids have shown promising metal nanocomposites are being intensively studied for probable activity against various bacterial strains.238 The exact mechanism applications in the medical sector. Palladium is one such noble metal behind this antibacterial activity of GNPs has evaded researchers, but and its nanostructure has drawn tremendous interest in the last one of the primary reasons could be stable antibiotic-GNP conjugate decade for a variety of applications.223–228 Despite the remarkable formation. In one report it has been suggested that the direct use of property of palladium as a metal and its diversified exploitation in antibiotic in the synthesis of GNPs offers a much-improved several biomedical applications,229,230 palladium nanocomposites antibacterial activity.239 GNPs are also investigated for their antiviral have made a late entry into the nanobiotechnology field. Here, we activity against human immunodeficiency virus (HIV), the cause of discuss the therapeutic property of palladium nanomedicines routed acquired immunodeficiency syndrome (AIDS). Functionalisation of in their catalytic, photothermal and biological activity. Firstly, GNPs with HIV-1 integral protein transduction domain (PTD) was polymer functionalised palladium resin has been used as a prodrug. tested in vitro in a human fibroblast cell line. It was observed that This palladium nanocomposite resin complex has been shown to surface modified GNPs (~5 nm) can traverse across the plasma activate a number of biologically inert drugs such as 5-fluoro-1- membrane, whereas larger particles (~30 nm) are unable to do so. propargyluracil231 and N4-propargyloxycarbonylgemcitabine.232 This study provides clear evidence that smaller sized GNPs can be These two drugs are otherwise biologically inactive, but combined used as a drug delivery vehicle for AIDS.240 Free SDC-1721, a treatment with palladium nanocomposite resin restores the anti- derivative of TAK-779 and a known CCr5 antagonist, which is the proliferative and cytotoxic activity of these drugs in colorectal and primary entry co-receptor for transmitted strains of HIV-1, has no pancreatic cancer cells. Toxicity of these resin palladium conjugates inhibitory effect on HIV infection. However, when conjugated with have been performed in the yolk sac of zebra fish and the results GNPs, the resulting SDC-1721-GNPs conjugates showed enhanced indicate no apparent toxicity while the chemical activity of the inhibitory activity against HIV infection.241 Another anti-HIV activity prodrug remains intact.231 Photothermal efficiency of palladium was studied with bare and PEG coated GNPs, in which it was nanostructures such as palladium nanosheets, has opened the door demonstrated that bare GNPs exhibit significant anti-HIV properties for their incorporation in cancer therapeutics. Hexagonal palladium as compared to PEG-GNPs; this may be due to the fact that nanosheets displayed efficient photothermal conversion efficiency nanoparticles coated with charge stabilisers (PEG) are larger in size due to their strong adsorption in the NIR region.233 This and hence cannot enter into the cells and inhibit viral growth.242 photothermal efficiency depends on size and surface coating, which Receptor binding inhibitory activity of GNPs against HIV was studied in turn affects the cellular uptake of these nanosheets.234,235 An using sugar coated nanoparticles. This study showed that sugar interesting finding is that palladium nanosheets tend to show better coated GNPs the function of dendritic cell-specific ICAM-3

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Journal Name ARTICLE grabbing non-integrin (DC-SIGN), which constitutes a major receptor trimethoprim have been studied.263 When AgNPs were used in for HIV-1.243 GNPs have also been applied for treatment of combination with gentamicin, ampicillin, vancomycin, and oflaxacin, Tuberculosis (TB) by utilising multiblock copolymer conjugated GNPs there was an improvement in antimicrobial activities. This enhancing as a successful delivery vehicle for TB drugs such as Rifampicin.244 effect of AgNPs emphasises the potency of Ag in increasing the Application of GNPs as a drug delivery machinery has led to their membrane permeability.264 One of the reports suggests that AgNPs incorporation in immunisation therapy due to their small size and enter the cell by disrupting the cell membrane and interfering with ability to enter cells. For example, GNP-conjugated chitosan exhibits the cytoplasmic content.265 The size-dependent antibacterial activity an enhanced serum antibody response which is several folds more of AgNPs has been investigated and it has been indicated that smaller powerful than the naked DNA vaccine.245 GNPs are potential carriers AgNPs exhibit enhanced antibacterial activity as a result of relative for the development of synthetic peptide vaccine against foot-and- increase in contact surface area.266 PEG-AgNPs of different sizes were mouth disease virus (FMDV). A synthetic peptide resembling FMDV tested for their antibacterial activities against Gram-positive (S. proteins was conjugated with GNPs, and after immunisation it was aureus) and Gram-negative (Salmonella typhimurium) bacteria, the observed that there was production of specific antibodies against the results demonstrated that size modulation of PEG-AgNPs can peptide.246 The role of GNPs in cancer immunotherapy has also been significantly enhance the antimicrobial properties of AgNPs against studied extensively.247 There are several reviews regarding the both these pathogens.267 There are several reports which throw light advancements of conjugated GNPs in vaccine delivery.248 One group on the antibacterial activity of AgNPs against MDR.268 It has been of researchers illustrated the adjuvant properties of GNPs in demonstrated that AgNPs and GNPs are equally effective against E. facilitating the delivery of both the ovalbumin (OVA) peptide antigen coli and Mycobacterium tuberculosis (MTB), but a higher and CpG adjuvant, resulting in an enhanced therapeutic effect in a antimicrobial activity has been reported by AgNPs. This result B16-OVA tumour model.249 Silver nanoparticles (AgNPs) represent suggests that AgNPs can be used for TB therapies. In consistency with one of the most common nanocomposites used in consumer goods the above observation, it has been established that AgNPs coated and in medical products, including wound healing bandages and a with bovine serum albumin (BSA) offer better biocompatibility variety of antiseptic sprays.250 AgNPs have been shown to provide against TB without losing their effectiveness, as opposed to polyvinyl protection against various infectious diseases, since they act as pyrrolidone (PVP)-AgNPs. antifungal, antiarthropod, antiviral and antiprotozoal agents.251 Additionally, the powerful antimicrobial as well as highly toxic The antifungal property of colloidal silver is comparatively less activity of silver nanocomposites have been extensively studied and studied in comparison to its antibacterial activity. Still, there are reported.250,252–255 AgNPs have been shown to possess higher numerous reports which confirm that AgNPs can be a potent cytotoxicity compared to the well documented GNPs.256–258 Three antifungal agent. AgNPs have shown significant activities against probable explanations are given in order to describe the antibacterial different fungal species such as Candida albicans, C. tropicalis, activity of AgNPs: (i) direct interaction of AgNPs with the bacterial Trichophyton mentagrophytes, C. glabrata and C. krusei.268 cell membrane results in membrane disruption and complex Biosynthesised AgNPs seem to have antifungal properties against formation with substances located intracellularly;259 (ii) AgNPs Phoma glomerata, P. herbarum, Fusarium semitectum, and interact with the thiol groups (-SH) and produce ROS;260 and (iii) Trichoderma species; they also showed synergistic effect when in subsequently, there is release of Ag+ ions which inhibit respiratory conjugation with a standard antifungal agent such as fluconazole.269 enzymes and also increase ROS generation (Fig. 7).261 Antifungal action of AgNPs in combination with heterocyclic compounds, namely thiazolidine, phthalazine, pyrazolo, and hydrazide, were investigated against Aspergillus flavus and C. albicans. The results indicate an enhanced antifungal activity in combination with above mentioned compounds as compared to heterocycles alone.270 In a separate study, AgNPs and natamycin were tested against various strains of fungi among patients suffering from severe keratitis and the authors observed a higher antifungal activity of AgNPs in comparison to natamycin.271 A possible explanation for the antifungal properties of AgNPs might be due to its role in disrupting cell membrane integrity and by inhibiting the normal budding process in yeasts.272 AgNPs are also emerging as one of the possible potent options for managing viral diseases due to their potential antiviral properties.273 AgNPs are capable of acting on broad range of viruses and offer a lower probability of developing resistance against viruses as compared to conventional antivirals. AgNPs synthesised by biological processes tends to exhibit higher Fig. 6 Schematic representation of the proposed mechanism of antibacterial activity of antiviral properties as compared to chemically synthesised the iodinated chitosan-Ag NP composite. Modified from260. particles.274,275 Kidney epithelial cells extracted from an African green monkey and co-incubated with AgNPs displayed significantly Mycosynthesised AgNPs using different strains of fungi have shown reduced plaque formation with Monkeypox virus (MPV).276 The significant efficacy against Staphylococcus aureus, Streptococcus preventive antiviral nature of AgNPs has been extended to HIV, pyrogenes, Salmonella enteric and Enterococcus faecalis.262 AgNPs where they are seen to prevent the host cells from binding with the associated with traditional antimicrobial drugs have been deployed virus in vitro.277,278 AgNPs effectively decrease HIV-1’s infectivity by to provide the possibility of more rational therapies. AgNPs acting directly on the virus by binding to the glycoprotein gp120.279 synthesised using Aspergillus flavus and upon conjugation with This structural alteration in turn, decreases the CD4-dependent several antibiotics such as ciprofloxacin, gentamicin, vancomycin and virion affinity, thereby preventing HIV-1 infection.279 Recent studies

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ARTICLE Journal Name have yielded promising results regarding the antiviral property of water purification was demonstrated.287,288 Green-synthesised AgNPs against influenza A H1N1 virus.280 The antiviral potency of AgNPs using F. oxysporum have shown promising result against AgNPs has been further demostrated against Herpes simplex virus Leishmania amazonesis promastigotes both in vitro and in vivo.288 types 1 and 2 (HSV-1 and HSV-2) and human parainfluenza virus AgNPs inhibit the biological activity of Leishmania tropica and this types-3 (HPIV-3) in a dose-dependent manner.274 A similar study was effect was enhanced under UV irradiation. The enhancement in anti- carried out against adenovirus type 3 (AD3) where it was illustrated leishmanial activity under UV light was attributed to the ability of that AgNPs processed cytotoxic effect against AD3 by not only AgNPs to release Ag+ ions, leading to the interaction of the AgNPs damaging the virus particles, but also disrupting the DNA structure. with the parasitic surface lipophosphoglycan and glycoproteins, In addition, AgNPs can damage the capsid protein which inhibits the which are responsible for spreading infection.289 AgNPs have virus attachment to the host.281 Capping agents play a significant role profound influence against plasmodia, biosynthesised AgNPs using in reducing infectivity and enhancing biological compatibility. AgNPs Acanthaceae and leaf extract of Catharanthus roseus have coated with stabilising agents such as PVP, PEG, and citrate have also demonstrated promising indication against Plasmodium falciparum been proved to be powerful antiviral agents, in a size-dependent in a size-dependent study.290,291 Wound healing promoted by AgNPs manner. It has been shown that a polysaccharide coating on AgNPs provides possible direction of research. Topical application of AgNPs protects the cell from the toxic effect of the nanoparticles, but also in a mice model exhibited wound healing and reduced scar formation reduces the NP’s activity against tacaribe virus (TCRV).282 In contrast, properties in a dose-dependent manner.292 When it was used for the same capping agent results in better antiviral activity efficiency burns, AgNPs of <20 nm in diameter at very low concentrations were against MPV.276 Other examples of coated AgNPs as effective able to work simultaneously as an antimicrobial as well as an anti- antiviral agents have been offered in several studies such as HIV- suppressant against local systematic inflammation in vivo. Studies of 1,279,283,284 HSV,285 and respiratory syncytial virus (RSV).286 PVP AgNPs acting as skin wound-healing agents in vivo have been. It was capped AgNPs have been used to prevent transmission of HIV-1 observed that low concentrations of AgNPs (~10 nm) promoted infection using an in vitro human cervical tissue-based organ wound closure and wound contraction by enhancing the culture279 and also as a coating for polyurethane condoms in order proliferation and differentiation of keratinocytes and fibroblasts.293 to inactivate infectious microorganisms.285 Another study concerning the skin penetration efficacy of colloidal silver and silver nanoclusters has shown that they are able to penetrate into human stratum corneum as well as the outermost surface of the epidermis.294 Polymer conjugated AgNPs in the size range of <50 nm can promote penetration through intact as well as damaged human skin; these future applications of AgNPs could have relatively long-lasting therapeutic benefits.

PtNPs have been applied for the treatment of Parkinson’s disease by functioning as a mitochondrial complex I, by lowering ROS generation, and by scavenging free radicals such as superoxide and 295 H2O2. PtNPs synthesised using leaf extract have also been used to treat Parkinson’s disease.296 The neuroprotective activity of the phytochemical conjugated PtNPs was studied in experimentally induced Parkinsonism in the zebra fish model. The results verified that upon pre-treatment with PtNPs, experimentally induced Parkinsonism could be reversed. PtNPs have been revealed to provide protection against oxidation-induced inflammation, this action of PtNPs decreases the osteoblastogenesis which causes bone loss.297 PtNPs play an important role in reducing cellular oxidative stress by acting as a quencher for ROS such as H2O2 and superoxide, thus resembling two biological enzymes, catalase and superoxide dismutases (SOD). Apoferritin surface functionalised PtNPs (AF- PtNPs) have been applied for studying the scavenging capability of H2O2 and superoxide on mammalian cell line Caco-2. It was observed that AF-PtNPs successfully compensated H2O2 and superoxide. Fig. 7 Schematic diagram of antimicrobial activities of noble metal nanoparticles. Owing to the receptor mediated internalisation of ferritin- functionalized nanoparticles into the cells, the membrane integrity The studies showed effective reduction in HIV infection, but the was preserved and other adverse interactions with cellular proteins mode of action is yet to be ascertained. One possible mechanism were avoided. After incorporation into Caco-2 cells, PtNPs decrease suggested is that AgNPs interact directly with surface glycoproteins the oxidative stress within the cell and increase cell viability.298 ROS and thereby interfere with the binding and fusion events during viral scavenging and apoptotic properties of PtNPs have also shown penetration into susceptible cells. Additionally, AgNPs are also able promising potential in treating ultraviolet (UV) induced inflammatory to inhibit post-entry stages of the HIV-1 life cycle by blocking various responses in the skin.299 An In vitro study in cell lines revealed a functional HIV-1 proteins or reducing the rate of proviral marked increase in ROS generation in UV-treated HaCaT transcription by binding to the RNA or DNA moieties. The keratinocytes cell lines, while a decrease in ROS production was antiprotozoal activity of AgNPs has also been studied recently. The observed in PtNPs treated cell lines. It was shown that mice treated efficacy of AgNPs as an antiprotozoal agent against Cryptosporidium with PtNPs gel prior to UV irradiation demonstrated a significant parvum was assessed and the disinfectant properties of AgNPs for inhibition of UVB-induced inflammation and UVA-induced photo

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Journal Name ARTICLE allergy compared to untreated controls. Studies on the antibacterial property of PtNPs performed with the pathogen, P. aeruginosa, observed that PtNPs showed size-dependent bacterio-toxic and bacterio-compatible properties.300

Ruthenium (Ru), rhodium (Rh), iridium (Ir) and osmium (Os) are the other so-called noble metals; they have gained considerable importance in the drug industry owing to their anticancer, antirheumatic, antimalarial, and antibacterial activities. Their assimilation into nanobiotechnology research is not as mature as other well-known nanomaterials such as gold, silver, platinum, and palladium. Ru is a 4d belonging to the .301,302 Despite the limited use of Ru nanoparticles in biomedical and clinical research, they have impacted on several other important application areas including catalytic dehydrogenation,303 methanol fuel cells,304 synthesis of diesel fuels,305 degradation of azo dye,306 and removal of organic pollutants from water,307 to name but a few. Recently, one group showed the antibacterial activity of Ru nanoparticles.308 In this study, they synthesised Ru nanoparticles using leaf extract; green-synthesised Ru nanoparticles, in the size Fig. 8 The arrangement of actin is followed as cells spread on a monolayer of collagen IV. range of ~40 nm, were tested against gram-negative and gram- Time points at 4 h (left) and 8 h (right) are shown. White stars indicate a cell body and positive bacteria in order to determine their antibacterial efficacy. arrows indicate actin alignment. Scale bar is 20 µm. Reprinted with permission from311 The results obtained demonstrated that Ru nanostructures tend to be most effective against gram-positive bacteria. Ru nanoparticles The phenomenon of Localised Surface Plasmon Resonance (LSPR) in attach themselves onto the bacterial membrane by electrostatic and noble metal nanoparticles has been most widely used for the coordinated covalent interactions, leading to generation of ROS development of new biosensors. LSPR arises from the within the bacterial cell and subsequent ultimate cell death.309 electromagnetic waves that travel along the surface of conductive Hence, we could see Ru nanoparticles being applied for development metals and semiconductors.312 Upon excitation with an external light of drugs against gram positive bacterial diseases. source, noble metal nanoparticles produce an intense absorption and scattering as a result of the collective oscillation of the Other lesser known nanomaterials of Rh, Ir, and Os have still not conductive electrons present at their surface and conductive bands. been put to wide use in biomedical research, although there have Noble metals, especially gold and silver, have been employed in been a few examples. The UV plasmonic properties of Rh many biosensors. nanocomposites have been extensively studied to show their potential uses in UV plasmonic and photocatalytic applications.309 Ir LSPR leads to exceptionally high absorption and scattering properties and Os nanoparticles remain less explored and need a thorough within the UV-visible wavelength which confers the particles with investigation regarding their future efficacy in clinical and human higher sensitivity in comparison to conventional organic dyes, health research. making them a perfect foil for colorimetric sensor applications.313,314 The sensing efficiency of GNPs depends upon their intrinsic localised surface plasmon resonance, with wavelengths around 510-530 nm Noble Metal Nanoparticles for Diagnostic and for gold nano formulations of around 4-40 nm, which can be used for biosensing.315 This effect is generally absent in the individual atoms Imaging Applications and the bulk form.316,317 The binding of molecules onto the particle Noble metal nanoparticles are the most common surface changes the LSPR, which is reflected by the scattered light in nanobiotechnological materials used for developing biosensors for dark field microscopy.318 In addition, SPR is drastically changed when clinical diagnostics, due to their ease in fabrication, physiochemical the average distance between the Au particles changes during the malleability, and high surface areas,310 allied with their unique formation of gold colloid aggregates.319 This attribute of GNPs has spectral and optical properties. Noble metal nanoparticles have had been utilised, for example, for the detection of DNA,320,321 by taking a promising impact on the development of new biosensors and on advantage of the binding affinity of single and ds-DNA on to their enhancing the specificity and sensitivity of already existing surface. Complementary charged GNPs interact electrostatically with biosensing techniques for biomolecular diagnostics (Table 3). Noble the free bases of single stranded (ss)-DNA, which in turn provides metal nanostructures can be engineered to specifically recognise colloidal stability to the nanoparticles in the presence of high salt biomolecules and provide a rapid and accurate estimation of the concentrations. In contrast, dsDNA molecules adsorb less to the concentration of an analyte. This can be achieved by exploiting GNPs surface and hence are unable to provide colloidal stability changes in the optical properties of noble metal colloids as a result under increasing ionic strength, leading to aggregation of GNPs, of affinity interactions modulating their size and electronic which results in LSPR and colour change simultaneously. GNPs configuration (Fig. 8A, B).311 The unique optical properties of conjugated with oligonucleotides that are complementary to the different surface modified noble metal nano formulations have been target sequence appear as a red solution in the absence of the target used for targeting biological components such as DNA, RNA, cells, sequence, whereas in the presence of the target, hybridisation proteins, small organic molecules, and other biological components. occurs and the solution changes to violet/blue due to LSPR.322 This approach has been successfully deployed for the detection of single nucleotide polymorphism (SNPs), UV induced mutagenic or

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ARTICLE Journal Name carcinogenic DNA dimmers, and in the detection of unamplified hepatitis C virus RNA isolated from clinical specimens.323–326 Citrate capped GNPs and AgNPs have been investigated for sensing thiourea and melamine using a colorimetric assay system.327,328 In this method, the presence of thiourea and melamine significantly reduces the overall surface charge of GNPs leading to their aggregation and this in turn is detected colorimetrically indicating the concentration of thiourea and melamine present. Detection of DNA, aptamers, and oligonucleotides has received considerable attention in recent years because it has important implications in medical diagnostic, food safety monitoring, and the drug industry. Many studies have been conducted using surface functionalised GNPs for the detection of DNA, aptamers, and oligonucleotides.329– 331 GNPs functionalised with thiol (–SH) modified ssDNA probes have been used to detect a single mismatch through a cross-linking approach in the presence of a complementary ssDNA.332,320 A non- cross-linking approach was used for the specific detection of genes associated with sickle-cell anaemia using fibrinogen functionalised GNPs and a thrombin binding aptamer.329 Fluorescence-based noble metal nanoparticle biosensors have been developed by utilising the quenching property of these nanomaterials. Two approaches have been used so far: (i) molecular nano-beacons, where noble metal nanoparticles are surface conjugated with fluorescent-labelled Fig. 9 (a) Near-infrared (NIR)-responsive cell-imprinted gelatin for capture and ssDNA which forms a hair-pin loop like structure; and (ii) noble metal photothermal selective release of single circulating tumour cells (CTCs) from peripheral nano-probes, which consist of noble metal nanoparticles blood. The cell-imprinted substrate is fabricated by imprinting target cancer cells on a Au functionalised with ssDNA that hybridise with another fluorescent- nanorod-embedded gelatin hydrogel. CTCs are then separated by anti-epithelial cell labelled ssDNA probe. Molecular nano-beacons have been used to adhesion molecule (anti-EpCAM)-modified cell-imprinted gelatin. This is followed by selective site release of an individual cell by exposure to a cell-sized NIR laser spot. (b) detect single-base mismatches in DNA with a higher sensitivity as Schematic showing the selective photodegradation of the thermoresponsive gel doped compared to conventional molecular beacons.333 In another with Au nanorods. Fluorescence microscope image of the fluorescein isothiocyanate (FITC) gelatin with a mask on top (bottom left). Fluorescence microscope image of the example, nano-beacons based on 13 nm GNPs have been FITC gelatin without the mask and after removal of the gel degraded via selected NIR successfully used to detect mutation associated with cystic irradiation (bottom right). Reprinted with permission from Reference fibrosis.334 In all these cases, the loop forming structure of the nano- doi.org/10.1038/s41578-018-0050-7 beacon brings the fluorescent dye moiety in close proximity to the noble metal nanoparticle’s surface resulting in quenching of the fluorescence intensity of the fluorophore. In the presence of a complementary DNA/RNA target, the hairpin structure is disrupted by hybridisation and restores the fluorescence of the labelled strands. . A gold nanorods containing gelatin hydrogel is developed for rapid recognition of circulating tumour cells ( ). An innovative Fig. 9 “chemical nose” technique has been developed using conjugates of GNPs and fluorophore which provides high sensitivity sensing of Fig. 10 Scheme illustration of GNP-based chemical nose for sensing of biomolecules 335 biomolecular targets (Fig. 10).335–337 This method was used for rapid based on competitive binding and fluorescence quenching. Modified from and accurate differentiation between normal, cancerous, and metastatic cells.338 Appropriately functionalised gold nanoparticles Antibody conjugated GNPs have been used for biological staining in can be used for a simple colorimetric test for small concentrations of electron microscopy and for radioactive labelling in vivo. The aqueous heavy metal ions, which includes toxic such as application of gold colloids in bio-diagnostics over conventional lead, cadmium and . GNPs are aggregated in the solution in organic dyes and quantum dots offers a number of advantages which presence of divalent metal ions by ion-templated chelation include reduced toxicity and contrast enhancing agents for imaging. process.339 The development of a fast and reliable method for Gold nano formulations can provide signal enhancement to standard glucose sensing is a prerequisite for the treatment and control of enzyme-linked immunosorbent assays (ELISAs), such as diabetes.340,341 Most electrochemical methods use enzymes such as immunochromatographic test strips where both primary and glucose oxidase or glucose dehydrogenase to catalyses the specific secondary antibodies are attached to GNPs.344 Surface modification oxidation of glucose. GNPs entrapped in a silica network can enhance of GNPs with Cy5-antibody as a fluorescence probe could replace the the non-enzymatic oxidation of glucose providing one possible conventional ELISA assay, since this technique does not require a alternative to the use of enzyme electrodes under appropriate secondary antibody and offers high sensitivity.345 Gold nanoshells are circumstances.342 A sandwich interface containing chitosan/Au capable of detecting nanogram quantities of various analytes present nanoparticles/glucose oxidase multilayer on platinum electrodes has in whole-blood in chemiluminescent analysis of antibodies. This been claimed to provide high sensitivity and a low detection limit for technique is far superior to ELISA in terms of technical proficiency.346 glucose, presumably due to the high electrochemically active surface The intense light scattering by large GNPs makes them a potent area and diffusion characteristics of GNPs at the sandwich probe for cancer detection. Immuno-targeting of antibody-GNPs to interface.343 label cancer cells is achieved by conjugating them with antigens overexpressed in cancer cells. For example, cervical epithelial cancer

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Journal Name ARTICLE cells (SiHa cells), which overexpress the transmembrane mainly attributed to the LSPR properties of the noble metal glycoprotein, epithelial growth factor receptor (EGFR), were nanostructures.363 A label-free SERS biosensor has been developed successfully detected by immune-targeted gold colloids.347 GNPs based on a glass surface coated with a layer of GNPs to detect and nanoprobes have also potentially simplified diagnosis of cancer by quantify nicotinic acid adenine dinucleotide phosphate (NAADP), detecting SNPs and mutation.348,349 A new approach has been added which plays a crucial role in intracellular Ca2+ release.364 This label- in the already existing repertoire of GNPs in the diagnosis of cancer, free SERS system allowed for a rapid detection of NAADP, making it wherein a combined solid-phase microextraction with gas a valuable tool for the study of normal and cancerous cells. In a chromatography/mass spectrometry has been employed for the similar approach, a surface covered with AgNPs were used instead of identification of volatile organic compounds acting as biomarkers for GNPs to detect bombesin, a neurotransmitter tumour marker and its lung cancer.350 analogues by SERS.365 This research group has also developed a protocol to monitor protein-protein and protein-small molecules Gold colloid bio-barcode amplification assays (BCA) can detect HIV-1 interaction using AgNPs staining of the samples for producing active p24 antigen at very low concentration levels (0.1 pg/mL). The substrates for SERS.366,367 Another group of researchers used SERS to conventional detection limit with ELISA is reported as 1-15 pg/mL,351 detect glucose levels by employing a self-assembled monolayer of while using GNPs there was a 100 to 150-fold enhancement in the decanethiol over an aggregated AgNPs film to increase glucose detection limit.352 Another, technique for reliable and sensitive adsorption, which is otherwise minimal for bare-SERS method for HIV-1 virus is based on gold colloid labelled silver staining substrates.368,369 SERS has also been used for detecting ssDNA by in conjunction with polymerase chain reaction (PCR). The results applying a slide derivatised with uncharged peptide nucleic acids demonstrated the highly sensitive and accurate potential for HIV-1 which recognise and hybridise with specific, negatively charged diagnosis using GNPs.353 Functionalisation of gold colloids with ssDNA. This system mediated the adsorption of positively charged Hepatitis B virus (HBV) DNA gene probes could be used to detect HBV AgNPs upon hybridisation.370 The use of functionalised noble metal DNA directly. This fluorescence-based method was highly sensitive nanoparticles has been investigated for a more versatile and specific and cost effective and could in future replace the highly complex SERS-based sensing of biomolecules. In this method, SERS signals multi-gene detection chips.354 Diagnostic applications of gold nano- were generated by using a probe (DNA, antibody) functionalised formulation probes have found their way into tuberculosis detection noble metal nanoparticles and a Raman-labelled probe. This sensor also. A target oligonucleotides sequence, suitable for mycobacteria system has been applied to detect a specific Anthrax biomarker by identification was used here. At high ionic strength, aggregation of means of peptide functionalised GNPs,371 and detect specific DNA the nanoprobe takes place in the absence of any complementary sequences such as HIV DNA using Raman-active dye labelled DNA on DNA sequence specific to target oligonucleotides and the turns the GNPs or AgNPs.372–375 Similarly, detection of hepatitis B virus antigen solution purple. On specific probe hybridisation to a complementary was reported using GNPs-antibody conjugates with 4- sequence (i.e. DNA from Mycobacterium tuberculosis), no mercaptobenzoic acid (MBA) acting as a Raman-active probe.376 Also, aggregation of GNP nanoprobe occurs and the solution remains the detection of viral pathogens using monoclonal antibody red.355 GNPs have been applied for the diagnosis of Alzheimer’s conjugated GNPs and a Raman reporter has also been studied.377 In disease biomarkers based on the SPR property of gold colloids. Here, a separate study, a molecular nano-beacon approach using a Raman gold nanoparticles are used to monitor the interaction between the dye-labelled DNA functionalised on AgNPs was applied to detect and antigen, amyloid-β derived diffusible ligands (ADDLs) and specific quantify a gag gene sequence of the HIV-1.378 Here, the presence of anti-ADDL antibodies.356 a complementary target decreased the SERS signal as a consequence of the disruption of the hairpin structure that would otherwise place GNPs have been used as nanoprobes for detection and the Raman dye in proximity to the NP’s metallic surface. This method differentiation of Mycobacterium tuberculosis (MB) from other has been further expanded successfully to detect the erbB-2 and ki- members of M. tuberculosis complex (MBC). In one report, 67 breast cancer biomarkers using gold nanobeacons.379 oligonucleotide modified GNPs were developed as a selective nanoprobe for DNA-based detection and differentiation of MB and A nanocomposite of PtNPs and graphene oxide has been successfully MBC. The technique was highly selective for distinguishing between used as signal transducer to develop a colour-based assay for the MB and MBC.357 In yet another approach, Mycobacterium bovis and detection of cancer cells by deploying folic acid functionalised MBC were successfully differentiated by GNP nanoprobes.358 A new nanocomposite of PtNPs and graphene oxide. Folic acid acts as a DNA-based biosensor for the highly sensitive detection of the specific recognition factor since folate receptors are over expressed on the IS6110 DNA sequence of MB has been achieved by using reduced cell membranes of different types of cancer cells.380 The result graphene oxide-GNPs as a sensing platform and GNPs-polyaniline as obtained above is due to the peroxidase-like activity of the a label for signal amplification.359 The nanoprobing activity of GNPs nanocomposite, which catalyses the oxidation of 3,3’,5,5’- for sensing MB shows potential for use in clinical diagnostics. Noble tetramethylbenzidine (TMB) by H2O2. Another example of the metal nanoparticles have been used for enhancement of Raman peroxidase activity of PtNPs has been applied in Enzyme-linked signals in Surface-Enhanced Raman Scattering (SERS) for different immunosorbent assays (ELISAs), a nanohybrid of magnetic types of analytes, and this has led to a wide variety of biosensors for nanoparticles and PtNPs was immobilised on the surface of graphene the detection of nucleic acids, antibodies, proteins, and other oxide. This sandwich of nanocomposite was effectively used for the biological molecules.360,361 Raman scattering arises from the inelastic colorimetric detection of cancer cells via reaction of the peroxidase scattering of photons that hit the analyte molecule in such a way that substrate, TMB.381 energy is either gained or lost so that the scattered photons are shifted in frequency. This interaction generates a narrow spectrum Electrochemical immunoassays (EIs) have been widely reported due of bands unique for each analyte, and this signal is greatly enhanced to their high sensitivity, simplicity, and low cost. Noble metal in presence of noble metal nanoparticles by an order of 105 to 106 nanoparticle-based electrochemical immunodetection offers added than the respective non-SERS Raman signals.362 This enhancement is advantages such as high conductivity and large surface-to-volume

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ARTICLE Journal Name ratio. These nanoscale materials are promising future candidates as for signal amplification in NEEIs utilising 3 different strategies; (i) as signal tags for the development of electrochemical platforms for electroactive labels, (ii) as carriers, and (iii) as electrocatalytic labels. immunosensing. The tuneability of noble metal nanoparticles in Direct application of noble metal nanoparticles as electroactive tags terms of size, shape, and surface conjugation has yielded positive has shown promising results in signal enhancement. This method results in amplification and enhancement of electrochemical comprises two stages. Firstly, strong oxidants are used to dissolve the immunosensing signals. Development of an accurate and sensitive noble metal nanoparticles into their metallic form, and secondly electrochemical immunosensor requires signal amplification and stripping voltammetry is employed for the sensitive detection of the background noise reduction owing to the relatively weak dissolved ions. Utilising this method, a group of researchers electrochemical action of the immunocomplex.382,383 Enzyme labels synthesised a nanohybrid of AgNPs and titanium phosphate and are generally used for this purpose, but due to the instability issues applied it as a label for electrochemical immunodetection of human related to most enzymes, there is interest in nano-templates as interleukin-6.403 In the presence of the target antigen, the alternatives for signal enhancement.384–386 Preparation of non- nanohybrid of AgNPs and titanium phosphate was anchored to the enzymatic electrochemical immunoassays (NEEIs) based on magnetically modified sensing array through sandwich-typed nanoscale system can be used for two purposes. First, they can be immunoreactions and upon addition of a strong oxidant, the Ag+ ions applied to transform the electrochemical transducer matrix, which are released from the complex. This system achieved an excellent will result in low background noise and fast electron transfer, and LOD for IL-6. In a separate study, AgNPs and graphene oxide secondly as tags for the amplification of the signals. Noble metal nanocomposite was used for electrochemical immunodetection of E. nanoparticles seem to be well suited to the development of NEEIs coli using solid-state voltammetry.404 GNPs have been used as because of their highly stable nature, conductivity, biocompatibility, carriers in NEEIs for loading of multiple electroactive labels for the and catalytic efficiency.387,388 The large surface area of noble metal preparation of functionalised signal tags in order to enhance the nanoparticles together with their ease of surface functionalisation immunoreaction system. The most commonly used electroactive with biomolecules (e.g. antibodies), electroactive tags and polymers, labels are thionine, ferrocene and metal ions. The functionalisation makes them a promising and interesting candidate for these systems. of GNPs with 6-ferrocenyl hexanethiol for the development of a GNPs and PtNPs of various sizes, shapes, and structures are sensitive electrochemical immunosensor provided an efficient signal inherently capable of catalysing oxidation, hydrogenation, and enhancing label for the determination of prostate specific antigen.405 dehydrogenation of innumerable analytes,389 and these properties of In this era of enhanced environmental concern, catalytic reactions noble metal nanosystems can be successfully employed for the play an important role in the field of environmental and material development of sensitive, reliable and cost-effective NEEIs. sciences.406 The contribution of noble metal nano-catalysts is still at an early stage. Recent studies conducted on the catalytic efficiency The introduction of GNPs in NEEIs as electrode materials for the of these nanoparticles have yielded some positive results which immobilisation of biomolecules has produced significant results.390 includes single-molecule fluorescence microscopy to decipher the GNPs are capable of binding a wide range of substances to build up size-dependent catalytic activities of GNPs.407 In another example, it an efficient electrochemical transducer surface, containing amino was shown that GNPs could greatly enhance the absorption of CO on 408 acid, protein, porous silica, metal nanoparticles, and carbon Au catalysts. Au nanoclusters supported on TiO2 have been nanomaterials.391–397 In this regard, an effective impedimetric applied for the oxidation of CO at low temperatures.409 Thiolate immunoassay was developed based on GNP-modified graphene ligand stabilised Au nanoclusters have been studied for the selective paper electrode for the rapid and sensitive detection of E. coli hydrogenation of unsaturated ketones and aldehydes to alcohols 0157:H7.398 A biocompatible nanocomposite comprising of GNPs and with 100% efficiency.410 A more recent study described the size- 4-amino-1-(-3-mercapto-propyl)- hexafluorophosphate was dependent catalytic activity of Au nanoclusters for thiophenol developed for sensing human IgG concentration with high oxidation in presence of O2. This study showed that neither sensitivity.399 Another such nanocomposite containing GNP- individual Au atoms nor GNPs are catalytically efficient, but the graphene oxide and polydopamine-thionine was effectively used for formation of gold nanoclusters result in an enhancement in the developing a label-free electrochemical immunoassay system for catalytic properties which was even greater than sulfhydryl determination of alpha-fetoprotein.400 The charge transfer and high oxidase.411 Fabrication of high-quality catalysts on supports such as conductivity properties of GNPs greatly enhanced the sensitivity of TiO2, Al2O3, and CeO2 are currently being investigated for enhancing this detection method. Palladium nanoparticles (PdNPs) are another the activity and selectivity of noble metal nano-catalysts. In this important noble metal nanoparticle, which has been utilised as aspect, it has been shown that TiO2 and Al2O3 act as a promising electrode material due to its high catalytic efficiency. Palladium support system for GNPs catalysts for CO oxidation with nearly 100% nanoplates, ultrathin metal films, have also been successfully used CO conversion.412 In addition, metal , carbon nanotubes, and for amperometric immunoassay for the accurate detection of alpha- graphene oxide (GO), have been applied to host GNPs for various fetoprotein.401 The sensitive detection of these cancer biomarkers catalytic applications.413–415 PtNPs have also found important was due to excellent electrochemical properties of the nanoplates, applications in electrocatalysis. The shape of PtNPs determines their which enhanced the electrochemical signal. PdNPs with a reduced electrocatalytic behaviour since the absorption behaviour of graphene oxide-based electrochemical immunodetection system reactants varies on the different facets of the nanocatalyst. This was have been fabricated for the development of prostate-specific demonstrated that the specific activity of Pt nanocubes for oxygen antigen. Low concentrations of these antigens could be detected reduction in acidic media was significantly higher than that achieved using this decorated electrode due to the synergistic electrochemical on polyhedrons or truncated cubes, because of the different activities of PdNPs and the reduced graphene oxide.402 absorption abilities on various Pt nanocatalyst facets.416 In a separate study, Pt multi-octahedrons exhibited better electrocatalytic activity Signal amplification is key to the development of efficient and highly than the conventional catalysts, owing to the higher ratio of different specific electrochemical immunosensors with low limits of detection Pt facets.417 (LOD) and high sensitivity. Noble metal nanoparticles have been used

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The ability of noble metal nanoparticles to absorb and scatter light in shown to increase image contrast by reducing both the radiation the NIR region makes them one of the most potent candidates as dosage needed and other toxic outcomes associated with using contrast agents in biomedical imaging (Table 4).418–420 The highly conventional contrast agents.429 The intense light scattering by gold permeable nature of human skin and tissues to NIR radiation has led nanoshells has been used to enhance image contrast in OCT to to the development of minimally invasive deep tissue diagnostic improve diagnostic imaging of tumours in a mice model as a result of imaging methods with noble metal nanoparticles acting as contrast nanoshell accumulation near the tumour site.424 Similarly, in PAI and enhancer vectors. The application of noble metal nanostructures in photoacoustic tomography (PAT), the image of circulating gold in vivo imaging techniques allows certain advantages over nanoshells in the vasculature of a rat brain has been shown to conventional NIR organic dyes, such as avoiding rapid enhance image contrast, allowing for a more detailed description of photobleaching, better detection sensitivity, improved stability in vasculature structures at greater depths.435 These applications of biological systems, and better multiplexing capability.420 gold nanostructures are attractive because they provide higher photostability, quantum yield, detection sensitivity, stability in Table 4 Biomedical imaging applications of noble metal nanoparticles via LSPR biological systems, and hydrophilicity than conventional organic properties. dyes. Additionally, the intense scattering property of these gold colloids has played an important role in enhancement of image Type of noble metal Applications References contrast in dark-field microscopy and dual-photon luminescence nanoparticles microscopy.436 The application of SERS in conjugation with noble Gold nanoshells Imaging of prostate cancer 447 metal nanoparticles has also been described for the detection and cells intracellular molecular imaging of living cells and tissues. In this case, Gold nanobeacons Imaging of sentinel lymph 449 60 nm GNPs coated with PEG and a tumour targeting antibody were nodes Gold nanoshells Contrast agents in dark- 206 able to detect tumours both in vitro and in vivo through SERS 437 field microscopy for HER 2, imaging. Here, GNPs were used to detect tumour biomarkers such a cancer biomarker as epidermal growth factor receptors on cancer cells and in xenograft Gold nanoshells Imaging of live HER 2 450 tumour models more efficiently than NIR-emitting quantum dots. overexpressing cancer cells Specific cancer biomarkers like phospholipase Cg1 (PCg1) were also Gold nanorods, In vivo imaging of cancer 442, 451 imaged in live HEK293 cell lines by noble metal nanoparticles using nanocages and cells SERS microscopy.438 SERS using GNPs attached to a Raman nanoclusters absorption reporter species has been demonstrated to highlight PEG-GNPs Imaging of tumour cells 453, 462 Gold nanoshells Imaging of tumours in 459 cellular and molecular structures which provide structural 439,440 mice model information on the cellular milieu inside live cells. Gold nanoshells Imaging of vasculature of a 460 rat brain Noble metal nanoparticles with light scattering properties enhance Environmental Applications of Noble Metal the contrast of imaging systems, such as dark-field or dual-photon Nanoparticles luminescence microscopy, and also facilitate combined imaging techniques to produce a synergistic effect over single imaging Growth of pollution from industry and agricultural has posed a life- method.421,422 Since the LSPR of noble metal nanomaterials is located threatening challenge to human society, in the form of hazardous within the NIR region, they have been applied in different imaging pollutants such as heavy metals ions, pesticides, dyes, toxic modalities like Photoacoustic Imaging (PAI), Photoacoustic chemicals, pathogens, and contaminants.441,442 Various optical Tomography (PAT) and dark-field and two photon microscopies. In sensors have been developed for detecting heavy metal ions which one study, gold nanorods conjugated with an antibody and include organic dyes,443,444 fluorescent polymers,445 and noble metal simultaneously tuned to the NIR region with PAI have been nanoparticles (Fig. 11).390,446–448 Among these sensors, noble metal effectively used to image early-stage prostate cancer cells. Here, the nanoparticles have attracted considerable attention owing to their gold nanorods resulted in enhanced contrast images between size, shape, chemical and optical properties, high surface-to-volume healthy/non-targeted tissue and cancerous/targeted tissue.423 Gold ratio, good stability, and excellent biocompatibility.390,449,450 In this nanorods as contrast agents for in vivo imaging using a laser based section, we describe some of the important sensing functionalities of PAI system have also been reported.424 In a complimentary noble metal nanoparticles (Table 5). approach, gold nanobeacons (2-4 nm) conjugated with PAI were applied for the detection of sentinel lymph nodes in ex vivo tissue GSH modified GNPs with a core size of 5-8 nm have been used for 2+ specimens.425 In dark-field microscopy, the NIR scattering properties detecting Pb ions in solution by a colorimetric method. GSH-GNPs 2+ of gold nanoshells has been exploited as contrast for targeting could immediately aggregate in the presence of Pb ions which 451,452 human epidermal growth factor receptor 2 (HER2), a biomarker for results in a red shift in their SPR peak. This method is size- cancer.193 These gold nanoshells were also used to image live HER2- dependent, with a better sensitivity when the core size of the GNPs overexpressing cancer cells using two-photon microscopy.426 Gold is bigger. Such colorimetric assays are popular because they can be nanoshells, nanorods, nanocages, and nanoclusters have shown easily observed with the naked eye or using a UV-vis spectrometer considerable promise as contrast agents for in vivo cancer imaging thus providing simple, cost-effective, sensitive, and selective due to their significant absorbance and scattering in the NIR detection of harmful environmental pollutants such as heavy metal region.418,427 These nanoformulations of gold are also used as ions. In another study, 11-mercaptoundecyl-trimethylammonium 2+ contrast agents for Surface-enhanced Raman Scattering (SERS), (MTA) conjugated GNPs have been investigated for Hg ion 453 Photoacoustic Imaging (PAI), Computed Tomography (CT), Magnetic sensing. The colour of the GNP solution changes from red to blue Resonance Imaging (MRI), and Optical Coherence Tomography in the presence (OCT).428–434 The use of ~30 nm PEG coated GNPs for in vivo CT was

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number of metal atoms) often produce higher fluorescence due to their smaller size and larger surface area and these fluorescent probes can be used for sensing heavy metal ions as environmental pollutants.464 Protein coated gold nanoclusters as a highly fluorescent probe have been successfully used for the detection of 2+ + 465 + Hg ions and CH3Hg species with low LOD. Traces of Ag ions are similarly tested using BSA conjugated gold nanoclusters, where the presence of Ag+ ions leads to the formation of Ag-Au alloy nanoclusters which in turn produce an increased fluorescent intensity.466 Ag nanoclusters also exhibit similar fluorescent probing activity for detecting Hg2+ ions due to strong interaction between Ag+ and Hg2+ ions.467 Metallophilic interaction between metal cores with a closed-shell electronic configuration can be applied for detecting heavy metals ions. As in the case with Ag and Au nanoclusters, a trace amount of Hg2+ ions could be effectively detected using this property, which leads to fluorescence quenching of the nanoclusters.468 Polymethacrylic acid-functionalised Ag nanoclusters were used to detect Cu2+ ions, which quenche the fluorescence of Ag nanoclusters Fig. 11 (a) Surface-enhanced Raman spectroscopy (SERS)-based detection of 469 magnetically separated bacteria. (b) Preparation and use of a gold/reduced graphene in solution. In a separate study, pepsin-conjugated Au 2+ oxide (rGO) nanocomposite-based biosensor and its application for the electrochemical nanoclusters were applied for sensing Pb ions via fluorescence detection of organophosphorus pesticides (OP). (c) Combined magneto-fluorescence enhancement and can also be used for Hg2+ ion detection by a approach for detection of bacteria using fluorophore labelled magnetic nanoparticles. fluorescence quenching phenomenon.470 The sensing capabilities of Reprinted with permission from 10.1038/s41565-018-0209-9 noble metal nanoparticles is not limited to heavy metal ions; they can also be utilised for H2O2 and pesticide sensing as well. For example, of Hg2+ ions, which is again evidenced in the UV-visible spectra with BSA stabilised gold nanoclusters can detect H2O2 and common a red shift of the absorption peak. The high affinity between Hg2+ ions pesticides such as dithizone, fenitrothion, and paraoxonethyl, using and GNPs have also been utilised for removal of mercury from water fluorescence detection.471 Low levels of pesticides such as 454 472 using a GNP-Al2O3 nanocomposite. The shape of noble metal endosulfan have been sensed by GNPs as well (Table 5). nanoparticles proves to be a potent regulator in sensing capabilities of heavy metal ions. For example, decahedral GNPs can detect Pb2+ ions at 1000-fold lower LOD than their spherical counterparts.455 Similarly, AgNPs with different shapes such as nanospheres, nanoplates and nanorods have been applied for constructing colorimetric sensors for Co2+ ions. Spherical AgNPs showed the highest sensitivity for Ni2+, Co2+, Cd2+, Pb2+, and As3+ ions,456 whereas Ag nanorods possessed greater selectivity for Co2+ ions over other metal ions in the solution. It has been shown that AgNPs provide a lower LOD for Hg2+ ions than GNPs because the molar extinction co- efficient of AgNPs is about 100-fold greater.457 This property has been utilised to make cost-effective assays for Hg2+ ion detection using mercury-specific oligonucleotides.452 In the presence of Hg2+ ions, the unfolded nucleotides were linked with Hg2+ ions, which resulted in aggregation of AgNPs in solution as reflected colorimetrically. PtNPs can also be used for sensing mercury. PtNPs used for this purpose catalyse the reaction between TMB and H2O2, Fig. 12 Schematic representing the Hg2+ sensing mechanism of the colorimetric assay, which leads to a blue coloured product. However, in the presence of (b) Photographs of AuNP solutions showing that the colour change occurring only in the 2+ presence of lysine (0.4 mM) and Hg2+ (10 µM) and (c) extinction spectra of the AuNP trace amounts of Hg ions, this catalytic activity of PtNPs is solutions. Reproduced with permission from460 inhibited.458 GNPs functionalised with different organic ligands such as thiolates, amino acids, peptides, and DNA, have been described as sensitive colorimetric detectors for heavy metal ions.452,459 For Toxicity Challenge of Noble Metal Nanoparticles example, citrate coated GNPs aggregate in presence of Hg2+ ions and lysine, because of the strong bond formation between Hg2+-Au (Fig. The incorporation of noble metal nanostructures in this diverse 12).460 In another example, peptide functionalised GNPs can be range of applications has led to increasing concern about their deployed for sensing Co2+, Hg2+, Pb2+, Pd2+, and Pt2+ ions, possible toxic impact on human beings and the environment (Fig. respectively.461 13). In general, human beings are exposed to these nanomaterials via inhalation, ingestion, and dermal contact.473 Reports suggest that Moving on to the next property of noble metal nanoclusters, that is noble metal nanoparticles tend to exert their toxicity when they fluorescence which confers attractive attributes for sensing heavy either circulate in the bloodstream to organs, tissues and cells, or get metal contaminants due to higher emission.462,463 A desirable sensor absorbed in the spleen or bone marrow (Table 6). These absorbed system with strong fluorescence can be developed by fine tuning the nanomaterials evoke oxidative stress, immune response, cellular size, shape, composition, and surface functionalisation of noble apoptosis, and DNA damage upon their entry into the mitochondria metal nanoclusters. Metal nanoclusters with smaller size (i.e. fewer

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Journal Name ARTICLE and the nuclei.474 Depending on the size of the nanoparticles, their Fig. 14 The fate of nanoparticles and their accumulation and clearance sites. (a) typical fate after intravenously injection is summarized in Fig. 14. Schematic illustration of kidney filtration or renal clearance of NPs, SEM images and histology of glomerular cell surface (endothelial lining). (b) Schematic illustration lung capillary beds filtration of NPs in the lungs. (c) Schematic illustration of nanpparticle clearance mechanism in liver via endocytosis by Kupffer cells (histology) and fenestration by endothelial cells (SEM); (d) Schematic illustration of the enhanced permeation and retention (EPR). SEM images of normal and cancerous tissues. MPS, mononuclear phagocytic system; RES, reticuloendothelial system. Reprinted with permission from Reference doi: 10.1038/natrevmats.2017.14

A size-dependent toxicity study was performed for GNPs on different cell lines such as fibroblast, epithelial cells, macrophages and melanoma cells. The study demonstrated that GNPs in the size range of 1.4-5 nm exhibit toxicity to all the above-mentioned cells, whereas 15 nm GNPs exposure to cells has no profound negative side effects even after 3 days of treatment.475,476 In a separate study, it was demonstrated that bare GNPs can induced cell-specific killing in a concentration dependent fashion and the accumulation of GNPs is localised in specific cellular domains (Fig. 15).199 Co-incubation of immune cells with citrate capped GNPs (10 nm) showed a little Fig. 13 Schematic representation of toxic effect on animal model system by metallic adverse effect on the immunocellular phenotypes and cell death, nanoparticle exposure. even after 48 hours of treatment, whereas the cytokine profile (IL-1, IL-6, IL-10 and IL-12) significantly changes which implicates the activation of the immune response upon GNPs treatment.477

Fig. 15 Intracellular localization of GNPs in A549 cells. Upper panel: The left column is the scattering of GNPs in the presence and absence of GNPs after excitation in the ultraviolet-visible range (300-450 nm). The right column shows the coexistence of nucleus (DAPI) and GNP scattering, in the presence and absence of GNPs. Lower panel: Magnified version of the red arrow marked cell. Reprinted with permission from199

It has been reported that 15 nm GNPs coated with triphenyl- phosphine are fairly unreactive in comparison to 1.4 nm GNPs, which cause mitochondrial disruption and generation of free radicals.478 Similarly, stress related genes were up-regulated upon treatment with 1.4 nm GNPs, but not with 15 nm GNPs, as revealed by gene array analysis.478 In another study, the epigenetic modulation was

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ARTICLE Journal Name observed in lung fibroblasts upon exposure to 20 nm GNPs. Here, In another independent study, it was concluded that AgNPs exert GNP treatment caused up-regulation of microRNA-115, down their cytotoxic effect in a size-, shape-, and dose-dependent manner regulation of PROS-1 gene and condensation of chromatin in the on red blood cells and hepatic stellate cells.498 nucleus.479 Gold colloids of 20 nm in size can also trigger oxidative stress autophagy in human lung fibroblasts,480 which results in elevated lipid peroxidation levels, up-regulation of many autophagy related genes (ATG-7), increase in inflammatory enzyme cyclooxigenase-2 (COX-2), and polynucleotidekinase 3’-phosphate (PNK) gene production.480 In another example, keratinocytes (HaCaT), when exposed to 1.5 nm GNPs of different charge (positive, negative and neutral), exhibited a noticeable disruption of cellular structure in a dose-dependent manner.481 The surface charge of GNPs determines the extent of biological response, with charged GNPs promoting apoptosis whereas neutral GNPs lead to necrosis.482 Similarly, when positively charged GNPs (2 nm) of varying surface hydrophobicity were tested in HeLa cells, the experimental outcome revealed that the higher the hydrophobicity, the greater the observed acute toxicity and production of ROS.483 It was found that larger surface charge density (effective electric field) of negatively Fig. 16 Cellular survival rate as function of effective electric field for negatively charged charged GNPs results in higher degree of fluctuation in the GNPs.484 cytotoxicity (Fig 16).484 Recent investigation has revealed that 10 nm GNPs are widely dispersed throughout the body, whereas larger A Trojan-horse effect has been suggested in relation to the dose and particles were observed only in the liver, blood, and spleen.485 In a time-dependent harmful side effects of AgNPs in the RAW246.7 cell similar study, Wistar-Kyoto rats treated with 10, 20 and 50 nm GNPs line. In this case, after exposure to the nanoparticles, intracellular for 3-7 days, showed hepatotoxicity and renal toxicity. Smaller sized glutathione (GSH) level decreased, leading to a cascade of reactions GNPs had a more deleterious effect than larger particles with which included increased secretion of nitric oxide and increased concomitant generation of ROS, which led to necrosis, renal tubular expression of TNF-α and matrix metalloproteinase,499 with a modulations, higher Kupffer cell hyperplasia, and central veins complete arrest of the cells at G1 phase of the cell cycle. A cytotoxic intimae disruption.486 In a separate observation, it was illustrated study of AgNPs in rat liver cells (BRL 3A) observed that after 24 hours that GNPs stabilised with non-toxic stabilisers, in this case PEG, also of incubation with AgNPs,500 there was a significant decrease in the showed size-dependent harmful effects. PEG-GNPs of smaller functional attributes of mitochondria and leakage of lactate hydrodynamic diameter (5, 10 and 30 nm) accumulated in the liver dehydrogenase (LDH). AgNP toxicity is mediated through oxidative and spleen, whereas much larger nanoparticles (60 nm) did not stress, which increases ROS and decreases GSH production.500 agglomerate in either of these organs.487 Size and surface charge Further investigations clarified the mechanism of cytotoxicity of distribution of GNPs also seem to have a profound negative influence AgNPs using human Chang liver cells,501 where it was elucidated that on aquatic life. In a study conducted in vivo in a zebra fish model, it the AgNPs create a loss of mitochondrial membrane potential (MMP) was observed that upon exposure to GNPs functionalised with by regulating the expression of the mitochondrial-dependent cationic ligands (~1.3 nm), fish embryos exhibited harmful side apoptotic pathway (Bax and Bcl-2).501 This decrease in MMP results effects, which included morphological changes such as abnormally in the release of cytochrome C, which in turn activates caspase-3 and small and less pigmented eyes.488 Depending upon the route of caspase-9. In a more recent and detailed study, it was illustrated that administration, the toxicity profile of noble metal nanoparticles AgNPs contribute to cellular damage.502 In this experiment, the varies. For instance, the toxicological features of 13.5 nm GNPs are bioenergetics of rat liver mitochondria was determined upon determined on the route of administration.489 In this study, mice exposure to AgNPs and it was shown that AgNPs create an increase were injected with GNPs through (i) oral administration, (ii) in the permeability of the inner mitochondrial membrane leading to intraperitoneal administration (IP), and (iii) tail vein injection. Tail mitochondrial depolarisation. This functional loss of mitochondrial vein injection showed minimal toxic effects to white blood cells and activity results in an uncoupling effect on the oxidative platelet counts, on the other hand GNPs administered orally or phosphorylation system.502 AgNPs, when incubated with liver cells intraperitoneally exhibited higher level of toxicity with reduction in such as human Chang liver and Chinese hamster lung fibroblasts for red blood cell count.489 The inclusion of AgNPs as an effective and 24 hours in a dose-dependent study, exhibited overloading of tested antimicrobial agent and in other therapeutic applications has mitochondrial Ca2+ ions and greater endoplasmic reticulum (ER) posed an intriguing question regarding their safety profile. The usage stress.503 AgNPs can lead to increased phosphorylation of PERK and of AgNPs for industrial benefits has directly or indirectly presented IRE1 along with an up-regulation of GRP78/Bip, which are ER stress an enormous threat to human health and environment alike.490,491 markers, and altogether this induced ER stress upon AgNPs exposure The size, shape, and surface composition of AgNPs are the major ultimately leading to cellular apoptosis.503 AgNPs also exhibit contributing factors which affect their intracellular uptake and cytotoxic effect in coronary endothelial cells (CECs) and aortic rings cytotoxicity.476 The noxious side effects of AgNPs have been studied isolated from rats.504 In this study, it was observed that AgNPs induce thoroughly and in a detailed manner using numerous models like NO-dependent proliferation in a dose and size-dependent manner in zebra fish,256 mice, rats,492 fresh water flea,493 stem-cells derived CECs.504 Intravenous administration of AgNPs in Balb/c mice revealed fibroblast, and L929 cell line.494 The deleterious effect of AgNPs leads that particles were mostly taken up by the reticuloendothelial system to harmful ROS generation and lipid peroxidation, which in turn (spleen and liver).505 However, other reports suggest enhanced liver causes DNA damage, necrosis, and apoptosis.495–497 enzyme activity, higher uptake by local macrophages, increased inflammatory response, and liver damage.505 The effect of inhalation

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Journal Name ARTICLE of AgNPs was performed using Sprague-Dawley rats with 18 nm and biocompatibility of the nanoparticles for their successful AgNPs.506 The rats were exposed to the silver colloids in a whole- applications in biotechnology. body inhalation chamber and the end results indicated that AgNPs reduce lung function and produce inflammatory lesions in the lungs. Capping agents of nanomaterials contribute significantly in the Oral administration of AgNPs (60 nm) in both male and female rats activity profile of noble metal nanoparticles. It has been reported were extensively studied for a one-month period.492 This that several attributes of capping agents increase the toxicity levels demonstrated that although AgNP treatment did not result in a of noble metal nanoparticles, hence in order to synthesise significant change in body mass index, blood chemistry analysis biocompatible nanoparticles, it is of primary importance that the revealed elevated liver damage as indicated by changes in alkaline capping agents are chosen wisely. In this regard, the use of non-toxic phosphatase (ALP) and cholesterol in both groups.492 PVP or polyvinyl alcohol (PVA) as a colloid stabiliser has been suggested by various research groups. PVP and gum Arabic (GA) Size-dependent studies on the toxic effects of AgNPs (22, 42, 71,323 coated AgNPs have shown promising result in reducing the toxic side nm) by oral administration in mice showed increased toxicity with effects of AgNPs.513 The wide acceptance of AgNPs as an higher immune cell infiltration (B cell and higher CD8+ T cell) and antimicrobial agent has led to an enormous amount of AgNPs being increased level of TGF-β and cytokine production (IL-10 and IL-12) in released in the sewage water bodies, which results in the loss of flora 22 nm AgNPs treated mice, whereas larger particles did not produce and fauna. This harmful effect of AgNPs can be addressed by using any alarming side effects.491 In another study, 20, 80 and 110 nm sulphate anions in the sewage water thereby preventing or reducing AgNPs were administered through tail veins and it was concluded the highly toxic effect of AgNPs.514 The functional attributes of noble that larger nanoparticles mostly accumulate in spleen followed by metal nanoparticles are directly positively proportional to their liver and lung, while 20 nm AgNPs mainly get deposited in the liver surface area. In the case of agglomeration or aggregation of noble and then the kidney and spleen.507 Concentration dependent dermal metal nanoparticles, reduction in surface area occurs and this is toxicity of AgNPs conducted on male guinea pigs showed that at low ultimately reflected in activity loss. Hence, the problem of particle dose, AgNP-treated animals exhibited a reduction in the thickness of aggregation should be one of the main focus for nanotechnologists. the epidermis and dermis with an increase of inflammatory In one study, it has been shown that bovine serum albumin (BSA) Langerhans cells.508 However, when given at higher dose, skin provides a better colloidal stability to GNPs as a capping agent than toxicity was apparently observed as a result of disrupted collagen does citrate anions. This is because the electrostatic repulsion fibres as well as higher macrophage infiltration with acidophilic offered by citrate anion can be compromised by Na+ ions from the cytoplasm.508 saline solution, which leads to aggregation of GNPs, while BSA adsorbed on to the surface of the GNPs helps to prevent There are relatively fewer reports regarding the toxicity of PtNPs. agglomeration even under harsh conditions.515 In another study, the One report studied the cytotoxic effects of 3 different noble metal aggregation behaviour of platinum colloids was studied in solution nanoparticles (GNPs, AgNPs and PtNPs) using a zebra fish model. It using tetradecyltrimethylammonium bromide (C14TAB), was confirmed that PtNPs induce an increase in the hatching time, a cetyltrimethylammonium bromide (C16TAB) and drop-in heart rate, and a reduced touch response in this model.509 nonylphenolethoxylate (NP9). TEM analysis revealed that the Another study conducted on mice reports that PtNPs cause acute aggregation of PtNPs reduced considerably when CTAB and NP9 hepatic injury as evidenced by an increased level of serum were used as surfactants.516 In addition to polyethylene glycol (PEG), biomarkers of liver injury and inflammatory cytokines.510,511 PVP, natural polymers such as dextran, chitosan, pullulan, and Cytotoxic effect of PtNPs on skin suggest that nanoparticles of larger surfactants like sodium oleate and dodecylamine have also shown size and coated with an uncharged non-toxic stabiliser such as PVP promising results in preventing aggregation of noble metal have no significant toxic effect, while on the contrary, much smaller nanoparticles.517 Another important aspect of nanotechnology lies in sized PtNPs showed deleterious side effects on primary keratinocytes controlling the size of the nanoparticles and maintaining leading to decreased cell metabolism.512 The presence of these reproducibility, since the chemical properties of bulk noble metals nanomaterials in our day-to-day life is becoming inevitable and are different in comparison to their nanoscale version. Citrate ions therefore a more detailed and thorough investigation needs to be represent one of the most widely accepted reductants for the conducted concerning the long-term usage of these engineered synthesis of metallic nanomaterials. Size-controlled synthesis of nanoparticles for the betterment of human life and society. AgNPs was successfully achieved using citrate ions owing to the slow crystal growth as a result of interaction between silver and citrate ions.518 In a separate experiment, size-controlled preparation of Control Perspectives for the Use of Noble Metal AgNPs was performed using silver and glucose under autoclaved Nanoparticles in Biotechnology condition. By regulating the concentration of glucose, the researchers were able to produce AgNPs of small, medium, and large Nanobiotechnology faces a major challenge due to the uncontrolled sizes in a controlled and reproducible manner. Also, the caramel and unethical use of noble metal nanoparticles in a wide array of formed during the autoclaving of glucose functions as the stabilising applications, which can lead to serious and deleterious toxicity to agent for AgNPs, which in turn reduces their toxicity and increases humans and environment. The unparalleled advantages presented the biocompatibility of the AgNPs.519 In a similar manner, size- by noble metal nanoparticles would be of no use unless the burden controlled synthesis of GNPs was also conducted by UV irradiation at related to their toxicity is addressed and resolved wisely. In order to room temperature in the presence of air (5-20 nm). In this study, nullify or minimise the side effects of noble metal nanoparticles, medium sized and larger GNPs (25-110 nm) were also successfully various strategies are being employed by researchers worldwide, obtained by using ascorbic acid as a reductant.520 Therefore, by such as capping the nanomaterials with suitable compounds which utilising the above-mentioned strategies for noble metal aid in reducing the toxicity, preventing aggregation of noble metal nanoparticles, the toxicity indices of these particles can be checked, nanoparticles, and last but not least, engineering the size, geometry,

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