key: cord-0740617-5q67q14a
authors: Kamat, Siya; Kumari, Madhuree; Jayabaskaran, C.
title: Nano-engineered tools in the diagnosis, therapeutics, prevention, and mitigation of SARS-CoV-2
date: 2021-08-31
journal: J Control Release
DOI: 10.1016/j.jconrel.2021.08.046
sha: 334321fa72dce4060527b89d21889887068e41d9
doc_id: 740617
cord_uid: 5q67q14a

The recent outbreak of SARS-CoV-2 has forever altered mankind resulting in the COVID-19 pandemic. This respiratory virus further manifests into vital organ damage. Nanotechnology has been moonlighting in the scientific community to combat several severe diseases. This review highlights the triune of the nano-toolbox in the areas of diagnostics, therapeutics, prevention, and mitigation of SARS-CoV-2. Nanogold test kits have already been on the frontline of rapid detection. Breath tests, magnetic nanoparticle-based nucleic acid detectors, and the use of Raman Spectroscopy present myriads of possibilities in developing point of care biosensors. This will ensure sensitive, affordable, and accessiblemass surveillance. Most of the therapeutics are trying to focus on blocking the viral entry into the cell and fighting with cytokine storm. Nanobodies as vaccines against S and N protein have regained importance. All the vaccines coming with promising phase 3 clinical trials have used nano-delivery systems for delivery of vaccine-cargo. The use of chemically diverse metal, carbon and polymeric nanoparticles, nanocages and nanobubbles demonstrate opportunities to develop anti-viral nanomedicine. Nanotechnology also presents myriads of options for targeted drug delivery. In order to prevent and mitigate the viral spread, high-performance charged nanofiber filters, spray coating of nanomaterials on surfaces, novel materials for PPE kits and facemasks have been developed that accomplish over 90% capture of airborne SARS-CoV-2. Nano polymer-based disinfectants are being tested to make smart-transport for human activities. Despite the promises of this toolbox, challenges in terms of reproducibility, specificity, and efficacy are yet to overcome.

The multisensor-enabled paradigm could personalize and stratify the COVID-19 management and holistically guide dosing and timing of immunomodulatory therapies and vaccination intervals. This could maximize the benefits of therapeutic interventions and minimize deleterious effects. Detecting multiple cytokine storm components is a massive advantage over the conventional pathogen sensors, which can only detect one factor at a time, cost issues, and time factor [28] . A multisensor system (electric tongue) based on potentiometric sensors was employed by Eckersall and colleagues [30] to improve mastitis detection in robotic milking of farm animals. It detected the presence of organic and inorganic ions in the milk. Bovine mastitis, a global concern of the dairy industry, caused by pathogenic infection, results in inflammation of the mammary glands. It was imperative to detect the presence of pathogens and bacterial toxins in milk. This system is advantageous over the conventional system involving human inspection and manual measurement of electrical conductivity in the milk using individual electrodes. The multisensory approach has earlier served productively in detection and classification of human urine, fermentation growth media and broths, etc.

Seo et al. fabricated a field-effect transistor (FET)-based biosensor of 100 × 100 μm 2 detecting SARS-CoV-2 in nasopharyngeal swab specimens. It was based on immunological diagnostic method which does not require sample pre-treatment or labelling. Graphene sheets of the FET were functionalized with specific antibodies against S protein of SARS-CoV-2 using a probe linker. The nano-device could rapidly detect the virus in the culture medium, clinical samples and 1 fg/mL in phosphate-buffered saline, 100 fg/mL clinical transport detect nucleic acids. This added ultra-sensitivity to the device due to which it could detect 600 zM and 20 aM nucleic acid in buffer and human serum samples [31] . A 10 min lateral flow rapid-immunodiagnostic kit was developed using lanthanide-doped polystyrene nanoparticles, in the detection of anti-SARS-CoV-2 IgG in the serum. The nucleocapsid protein of the pathogen was immobilized onto the nitrocellulose component of the kit to capture the specific immunoglobulins. This technique is reported to serve well in cases of clinical suspicion which test negative by RT-PCR and require chest computed tomography for confirmatory detection [32] .

In 2009, state of the art, localized surface plasmon coupled fluorescence (LSPCF) fiberoptic biosensor was developed by Huang et al. to detect SARS-CoV nucleocapsid (N) protein [33] . It was observed that the N protein was detected as early as 1 day after infection, making it the suitable candidate for rapid detection. Gold nanoparticles used routinely possess optical properties such as localized surface plasmons (LSPs). The authors proposed a novel fibreoptic biosensor by combining LSPCF with fluorescence sandwich immunoassay featuring mABs against SARS-CoV N protein. The biosensor demonstrated an enhanced detection limit of 0.1 pg/mL N protein diluted in serum as compared to just LSPCF fibre-optic biosensor which is as low as 1 pg/mL and conventional antigen capture ELISA using the same mABs was 12.5-25 ng/mL. These unique affinity binding agents can be produced in bulk at low cost, were stable to wide range of pH, 2-5 nm and < 10 kDa and hence surpass antibodies. Unlike Si nanowires, metal oxide nanowires (In 2 O 3 , ZnO, and SnO 2 ) did not require insulating and can be easily derivatized. The authors claimed that the device could detect a subnanomolar concentration of N protein in a background of 44 μM bovine serum albumin. Patolsky and co-workers developed a nano-device for real-time electrical detection of influenza A virus using nanowire FET. The authors also discussed the possibility of simultaneous detection of various distinct viral diseases at a single virus level [35] .

A highly sensitive multivirus microfluidic electrochemical immunosensor was developed by Han et al. [36] for simultaneous detection of H1N1, H5N1 and H7N9. ZnO nanorods with high isoelectric point (IEP) were employed on the upper inner surface of a PDMS senor.

These interacted electrostatically with low IEP antibodies of the viruses. The device could detect upto 1pg/mL of each virus due to enhanced sensitivity with ZnO nanorods. These ZnO nanostructures have demonstrated significant biocompatibility and biosafety in biological environments, making them reliable and trustworthy in biomedical engineering applications [37] .

Breath sensors have been developed to diagnose respiratory illnesses. Gas chromatographymass spectrometry studies of human breath showed several volatile compounds which change in diseased cases. Peng et al. utilized an array of gold nanoparticles that could differentiate the endogenous volatile organic compounds (VOCs) in the breaths of normal and lung cancer patients. They further identified 42 VOCs which represented lung cancer biomarkers [38] .

Electrochemical detection of chikungunya virus was accomplished using molybdenum disulphide nanosheets imprinted with gold electrodes. Methylene blue was employed to detect guanine in single and double stranded viral DNA which corresponded to a J o u r n a l P r e -p r o o f Journal Pre-proof voltammetric signal. This disposable sensor could detect the pathogen in the rage of 0.1 -100 µM [39] .

A non-invasive method to detect glucose concentration was developed using nanoparticle embedded contact lens. This reflectance spectroscopy-based biosensor utilized glucose oxidase and cerium oxide (III) to detect he glucose concentration. Detectable changes were observed in the reflection spectrum of contact lenses [40] .

A rapid tool for detection of pathogenic bacteria was developed using bioconjugated nanoparticles. This ensured in situ pathogen quantification within 20 minutes. The authors tailored fluorescent-bioconjugated silica nanoparticles. Compared with conventional immunoassays where a few dye molecules are linked to antibodies, these tailored nanoparticles contained many dye molecules which produced a stronger signal of the antigenantibody binding event. The device could accurately detect 1-400 E. coli O157 cells in samples of spiked ground beef [41] . Even though this technique requires laboratory equipment such as fluorimeter, it surpasses the deployment of trained human resource such as pathologists and BSL-3 biohazard set ups.

Raman Spectroscopy presents distinct spectral features for target molecules and is therefore recognized as a promising tool in detection. Kang et al. [42] established the direct utility of glucose Raman spectra in vivo monitoring. In the fight against COVID-19, this technology could be used as a signal transduction mechanism, for a lateral flow test built with antibodycoated nanoparticles. Its detection limit in whole blood was 5 pg mL −1 . These sensors are now modelled to link to smartphones to increase their feasibility and robustness [43] .

A biosensor comprising of antibody-coated ZnO nanocrystals was developed by Cao et al. [44] . It was built using a rapid and inexpensive colloidal dispersion fabrication method.

Impedance spectroscopy was utilized to detect the C-reactive protein (CRP) antigen at a J o u r n a l P r e -p r o o f Journal Pre-proof lower limit of 1ng/mL. CRP is a key biomarker in COVID-19 patients, and hence this biosensor could be applied in the pre-diagnostic treatment.

Multiplexed detection systems have been made possible using quantum dot (QD) barcodes and genomic barcodes. QDs have been routinely used in proteomic and nucleic acid detection due to their unique property of photostable bright fluorescence. Hauck and co-workers describe QD barcodes as polystyrene microspheres containing varying ratios of QDs, with each individual colour relating to an antigen or nucleic acid target. The detected biological entity could be a gene, protein or an entire pathogen [45] . Based on the principle of quantum dots and microfluidics, a multiplexed, high-throughput blood-borne infectious disease detection system was generated by Klostranec et al. The system could detect serum biomarkers of hepatitis B, C and HIV with a sample volume of <100 μL within 1 hour with higher sensitivity than the FDA-approved methods. This proof-of-concept device could be further investigated to develop a portable handheld point-of-care diagnostic system which could revolutionize disease spread in developing countries [46] .

Since smartphones have an enormous global market, using them in controlling the pandemic has become an appealing option. The proposed mobile immunosensors [47] for IL-6 consist of a colorimetric detection paper using gold nanoprobes which generate coloured spots that get detected with the smartphone app. It used augmented reality to control the photographic parameters by compensating for variable light. The system can detect modulations in IL-6 in practice, a few concepts have been recently proposed by Russell et al. [48] . The first concept is a needle-shaped microelectrode for real time detection of IL-6 levels. This design works on the interaction between IL-6 and antibodies linked to the electrodes that changes the impedance of the sensor surpassing the use of labels [35] . The second concept is an electrochemical biosensor consisting of a wire electrode altered with aptamers that undergo a configurational change upon binding their target. This alteration brings about a change in a redox active dye (methylene blue) which generates a square-wave voltammetry. This sensor could detect real-time levels of vancomycin in rats [49] . In the midst of the current pandemic, the global demand for an economical, easy-to-use, rapid, sensitive and reliable detection system is increasing. While biosensors (magnetic/optical/electrochemical/mechanical) reduce the long turnaround times of detection, they also possess several challenges. The use of fluorescent dyes, radioisotopes, unstable enzymes, magnetic labels adds additional complexities of size, biocompatibility, detection of ultralow quantities of target components, optimal surface: volume ratio, thermal heating. For a successful point of care biosensor platform, one needs to optimize all these parameters. 

Imaging has become an indispensable tool in early diagnosis, clinical trials and general medical practice. This avenue is routinely deployed in early-stage detection of certain cancers. The routinely utilized techniques include X-ray imaging, magnetic resonance imaging, micro-computed tomography, ultrasonic imaging, positron emission tomography, electron tomography, optical coherence tomography. Even though these excellent bioimaging procedures offer a wide scope, the cost, technological barriers, biocompatibility with markers contribute to the limitations of these techniques [52] .

Nanoimaging introduces a deeper understanding of complex biological systems, surpassing the need for destructive sampling as seen in conventional chemical imaging techniques. It also ensures spatial-temporal sampling of the local environment for downstream analyses.

Since viral infection is a complicated process, involving various interactions with cellular structures, nanoimaging can give a good insight into SARS-CoV-2 pathogenesis [53] .

Fluorescence imaging, commonly referred to as optical imaging, is a rapidly growing avenue as an alternative to the above-mentioned techniques. Typical labels, fluorescent dyes, quantum dots (QDs), plasmonic nanomaterials, near-infrared (NIR) molecules have been utilized successfully. However, the high photo-bleaching rate, background noise, limited luminescence life and toxicity, have repeatedly posed challenges in its use [54] . Lanthanides demonstrated fluorescence, high biocompatibility. These can be utilized for in vivo anatomical imaging due to their deep tissue penetration, elevated spatial and temporal resolution owing to the unique emission window [55] . Manivannan [60] . VLPs can be loaded along with thousands of copies of contrast agents to increases the local concentration and therefore the signal-to-noise ratio. This can be used predominantly when these NPs are tailored to target specific tissues and cells [61] . Gadolinium (Gd), a contrast agent can be quite toxic; but VLPs are generally cleared rapidly from circulation and tissues thus ensuring no systemic toxicity.

A tobacco mosaic virus loaded Gd-dodecane tetraacetic acid, tailored to target VCAM-1, could detect and delineate atherosclerotic plaques in ApoE -/mice in MRI. Going beyond paramagnetic metal complexes such as Mn and Gd, new generation agents are being developed to improve resolution and provide functional information [61] .

QDs have also been utilized in labelling internal/ external components of the virus particle to They reported that the lower limits of detection for the sampled analytes were in the range of 1.5 nM to 180 nM. This break-through system can provide a holistic understanding of the metabolites and chemical signals that drive the pathogenesis of SARS-CoV-2 and other pathogens.

It is wisely said 'viruses are the most beautiful nano-creatures'. Nanoparticles have widely been used as therapeutic agents and in drug-delivery systems against a myriad of diseases, including viral infections. The emergence of SARS-CoV-2 has again lit the face of nanotechnology with the hope to aid a helping hand in this ailing situation of COVID-19. To prevent the SARS-CoV-2 infection, nano-drugs can find the following targets. Some

Journal Pre-proof evidences can also be taken from encouraging results of nanomedicine against earlier cases of disease outbreaks.

Anti-viral nanoparticles have focused on the three main mechanisms to design therapeutics against SARS-CoV-2.

The SARS-CoV-2 entry inside the human cells is facilitated by binding to the angiotensinconverting enzyme 2 (ACE2) receptor on target cells [16] . Han and Kral [69] in their computational study demonstrated the nano-sized peptide inhibitors extracted from ACE2 could block ACE-2 and SARS-CoV-2 binding. In another study, lipopeptide EK1C4 For entry of viruses inside the cells, they utilize several nanopores and nano-ranged Cell-Penetrating Peptides (CPPs). To optimize the size range of nano-therapeutics, one must consider the route of entry, subcellular trafficking and distribution of the particles to minimize their dilution [76] .

Currently, there is no approved nano-drug available to inhibit replication of SARS-CoV-2;

however, autophagy-modulation mediated inhibition of SARS-CoV-2 replication by precise and targeted nanomedicine has been suggested by Shojaei et al. [77] . Multiwall and singlewall carbon nanotubes (MWCNT, SWCNT), carbon dots (CD) and carbon nanodiamonds are promising nanomaterials to inhibit the virus replication directly. Carbon nanotubes are known to acidify the cytoplasm and alter the cellular temperature owing to its photo-thermal effects [77] . Nanodiamonds and carbon dots can modulate the viral replication pathways and immune responses of primary macrophages [78] . Seven different carbon-dots showed a concentration-dependent inhibition of human coronavirus HCoV-229E by inhibiting the entry receptor and replication of the viral particles [79] . Quantum dots-conjugated RNA oligonucleotide functionalized in a biochip was found to inhibit SARS-CoV 'N protein', essential for its replication [80] . Metal nanoparticles show multifarious modes of actions including replication inhibition, DNA and RNA damage and generation of ROS contributing

The cytokines storm has emerged as a major cause of mortality among COVID-19 patients causing acute respiratory distress syndrome (ARDS) [76] . Several sub-populations of the immune system, particularly, IL-6 has been associated with the hyperimmune activity.

Nanoparticles can help the immune-modulatory drugs to reach their targets specifically, silencing only a subset of the immune response to lower pro-inflammatory cytokine production. Multi-drug nanoparticle comprising squalene, adenosine and α-tocopherol has been designed to treat lethal hyper-inflammation in animal model in a targeted approach [83] .

Zadeh et al.

[84] postulated nano-engineering of gut microbiota to increase chronic phase proteins and interferon signalling in lung cells to protect against cytokine storm. Further, cytokine storm was successfully treated by [5-(p-Fluorophenyl)-2-ureido] thiophene-3carboxamide (TPCA-1) loaded platelets derived extracellular vesicles [85] .

works antagonistically against cytokine storm; however, their potency or production must be enhanced multi-fold to cope with the response generated during COVID-19. 'LIFNano' is a nano -technologically synthesized substitute of LIF which is almost 1000 times more potent than its counterpart, which can protect the lungs against the hyper-inflammation [86] .

Further, immuno-modulatory actions of octadecylamine-functionalized nanodiamond (ND-ODA) and dexamethasone (Dex)-adsorbed ND-ODA (ND-ODA-Dex) have already been tested against rheumatoid arthritis for their anti-inflammatory actions in macrophages in vitro [87] . Cytokine storm is also associated with death in certain respiratory ailments and However, the precise inhibition of cytokines must be considered before designing nanomedicines to avoid other bacterial and viral infections in already suppressed immune system. Immunotoxicity should also be considered while working with nanomedicines as it can also lead to cytokine storm [88] .

PDT and photobiomodulation (PBM) can emerge as novel approaches as therapeutics against COVID-19. Using non-invasive PBM, lasers can directly act on the chest area, inhibiting cytokine storm as well as lasers acting on bone marrow can immune-modulate and increase the synthesis of stem cells [89] . 

system in targeted drug delivery and self-monitoring for cancer cell therapeutics, which can also be exploited against SARS-CoV-2. This technology can be used to synthesize "monoclonal-type" plastic antibodies to combat COVID-19 [93] . Using MIP, specific monoclonal antibodies can be synthesized to selectively bind the SARS-CoV-2 spike protein, and thus inhibiting the entry of viral particles inside cells. This technology can also be used for mass-screening and rapid detection of COVID-19 cases.

Mild to severe toxicity of drugs used for the treatment of COVID-19 has been reported [94] , SARS-CoV-2 and reduction in their infectivity [98] . Inorganic nanoparticles have also emerged as a potent carrier of therapeutic cargo. Silica/polyP nanoparticles were used to encapsulate inorganic polyphosphate (polyP) which inhibited the binding of S protein to ACE2 (angiotensin-converting enzyme 2) [99] . PLGA nanoparticles have been used to deliver interleukin for immunomodulation of viral diseases [100] . Polymeric nanoparticles can be an excellent source of targeted drug delivery in vaccine and therapeutics development against SARS-CoV-2. Modulation of several parameters including viscosity, shape, size and loading capacity, further provides polymeric nanoparticles with an added advantage to be used as carriers in therapeutic development against SARS-CoV-2.

Lipid nanoparticles, liposomes and biomimetic lipid polymer hybrids are one of the most extensively used nano-carriers in vaccine and therapeutic development against SARS-CoV-2.

Most of the vaccines undergoing clinical trials by major pharma giants have either liposomes or lipid nanoparticles (LNPs) as the carrier of vaccine component to provide stability and effective cargo delivery ( Table 2 ). The Pfizer and BioNTech vaccine, which recently showed 95% efficacy in phase 3 clinical trials, has used LNPs to deliver BNT162 mRNA-based vaccine [19, 20] . The 'Moderna' vaccine which has also shown 95% efficacy in phase 3 clinical trials has also used lipid nanoparticles based platform to deliver mRNA-1273 [20]

( Fig. 5) . LNPs also enhance the cellular and mucosal uptake and reduce the vaccine system's clearance by mucosal cilia [7] . LNPs have been used as a siRNA carrier to suppress cytokine biocompatibility have assured the safe use for cargo delivery of therapeutics and vaccine components. However, their compatibility with the deliverable components should always be checked before proceeding towards further development.

Nanodiamonds, carbon dots, graphene, graphene oxide, single wall and multiwall carbon nanotubes are the major carbon based materials which can be used for detection, drug delivery and mitigation of COVID-19. Nanodiamonds can carry exceptionally high hydrophilic and hydrophobic cargo owing to their high surface area to volume ratio [5] .

Besides this, they also possess the intrinsic ability to activate the immune system [104] .

Graphene and graphene based nanomaterials conjugated with polymers have shown excellent

properties for viral growth and cytokine storm inhibition along with the delivery of therapeutics [105] . Functionalized carbon nanotubes are already known for targeted and controlled drug delivery [106] . Earlier, Loczechin et al. [79] had demonstrated anti-viral activity of functionalized carbon dots against human coronavirus. The diverse carbon-based nanomaterials can be a great choice as a carrier for vaccine development or as a hybrid therapeutic solution based upon their properties to deliver multiple range of cargos and biocompatibility. Their ability to modulate immune responses along with targeted drug delivery can be exploited against SARS-CoV-2.

As described earlier, virus-like nanoparticles have also demonstrated their multiple uses in detection and vaccine development against SARS-CoV-2 (Table 2) . Naskalska et al. [107] developed HCoV-NL63 VLPs using a baculoviral system which could effectively deliver cargo and electively transduce cells expressing the ACE2 protein. Recently, SARS-CoV-2

VLPs were developed using a mammalian expression system, which possessed molecular and J o u r n a l P r e -p r o o f morphological properties of native virion particle [108] . VLPs have also been used for delivery of CRISPR/Cas 9 proteins, which can emerge as a major therapeutic solution to COVID-19 [5] . Another landmark against COVID-19 was recently achieved when the first mass vaccination program was started in the UK with the vaccine developed by Oxford-AstraZeneca. This vaccine is a chimpanzee adenovirus-based vaccine (ChAdOx1 nCoV- 19) expressing 'S' protein of SARS-CoV-2 [21] .

Nanobubbles are the gas filled cavity in the aqueous medium which can be exploited for targeted drug delivery using ultrasound waves [109, 110] . A company named 'Nanobble'

[111] has postulated the use of ozone filled nanobubbles against SARS-CoV-2. Ozone being a strong oxidizing agent, has the anti-viral activity and has been used in water disinfection [112] . However, ozone being a strong oxidizing agent, sufficient precautionary measures and data analysis should be performed to avoid more harm than good of this therapy.

Nanocages are the hollow nanostructures which can be engineered on their surfaces, the interior and the exterior to enhance biocompatibility and targeted cargo delivery [113] . They have high loading capacity due to their spacious and porous interior and the possibility to engineer their exterior for targeted delivery [114] . SET-domain containing 6 (SETD6) is known to inhibit viral infection mediated inflammation, but its use is restricted owing to the short half-life and poor intracellular delivery. In 2020, Kim et al. [115] developed ferritin based nanocages for delivery of methyltransferase SETD6 for COVID-19 therapy. However, the toxicity assessment of nanocages must be considered before their use. and 'Sputnik V' to develop a vaccine against SARS-CoV-2 uses the non-replicating adenovirus based platforms that encode the spike protein of the SARS-CoV-2 and elicit immune response [5] . Table 2 summarizes the use of nanotechnology in the key developments of SARS-CoV-2 vaccine and its earlier contribution against coronaviruses.

Adjuvants also play an essential role in the successful development and administration of vaccines. The tailored designed nanoparticles provide multifunctional approaches for an adjuvant, increasing its bioavailability and controlled release of antigen and targets specific immune activities [5] .

Protection against SARS-CoV-2 and the mitigation of this disease are as important as the other two pillars 'detection and therapeutics development' to successfully win this difficult battle. Nanotechnology with the cost-effective, rapid and robust technologies can aid a helping hand in protection and mitigation against this pandemic.

SARS-CoV-2 can survive on both rough and smooth surfaces, providing an excellent mean for indirect transmission of the virus. Following tools of nanotechnology can provide an edge over the traditional disinfectant methods (Fig. 6) .

Titanium dioxide (TiO 2 ) nanoparticles are the excellent examples of surface disinfection by photo-catalysis and have been used against disinfection of many viral agents. TiO 2 NPs J o u r n a l P r e -p r o o f coated on windows, walls and used in water purification shows significant anti-viral activity when illuminated with UV light [119] , which can be rediscovered against SARS-CoV-2.

TiO 2 and SiO 2 nanocoating are used as self-disinfecting materials in hospitals as photoactivated particles can kill microbes by surface-leaching [120] . However, their toxicity and standardization of the techniques should be done on a case by case basis.

Further, Miyako et al. [121] developed NIR laser-driven carbon anti-viral nanohorns., which was able to show photo-catalysis against pathogens. Nanoparticles showing photo-catalytic properties can be used as paint or spray materials to disinfect the SARS-CoV-2 prone exposed areas.

Nanorods of certain metals such as gold (Au) and silver (Ag) can heat up and clean the surface when activated at a certain wavelength [76] , a phenomenon known as a plasmonic photothermal treatment. This newly developed technology can be used to coat the most critical surfaces to protect against SARS-CoV-2.

Metals have been used for their anti-microbial activity since ages [122] . suitable polymers [130] ; however, nanopolymers safety should completely be assured before their commercial use.

Plasma, considered as the fourth state of matter is an ionized gas where the atoms and/or molecules are uncovered of their outer-shell electrons. Radiofrequency plasma treatment using Ar/O 2 gas mixture against microbes and their toxins in a sealed bag has been reported J o u r n a l P r e -p r o o f Journal Pre-proof by Belgacem et al. [131] . Plasma activated water has emerged as an alternative disinfectant of SARS-CoV-2 by inactivating S protein [132] . Though this technology is nascent, regulated development in this field can provide a new paradigm in the sanitization of exposed surfaces.

Since the outbreak of COVID-19, facemasks and gloves have become a household name to mitigate the spread of SARS-CoV-2. Similarly, PPE kits have become ubiquitous in hospital surroundings. COVID warriors have to face many problems, including severe skin rashes as a side effect of prolonged use of PPE, facemasks and gloves. Nanotechnology can provide the more comfortable, breathable, efficient, hydrophobic and cost-efficient solution to these problems (Fig. 6) .

As discussed earlier, metals, carbon based nanoparticles and polymer based encapsulated anti-viral materials can be used in coating of gloves, face-masks and PPE kits. The fibres coated with photo-activated TiO 2 , two-dimensional carbides and activated carbon particles have shown enhanced adsorption and degradation of viral particles [76, 133] . Aydemir et al. [134] proposed coating of masks and nasal filters with ACE2 enzyme loaded nanoparticles for protection and mitigation against COVID-19. Ahmeda et al. [135] designed an anti-viral facemask composed of PLA and cellulose acetate polymer containing copper oxide and graphene oxide nanoparticle by electrospinning technique to control COVID-19 in Egypt.

Hydrophobicity is an important parameter to develop PPE kits as it inhibits the anchorage of tiny droplets responsible for viral spread. Similarly, porosity and breathability are important aspects for the comfort of the mask and kit bearer. For creating hydrophobicity, 'nanowhisker' technology is used where surface tension of tiny fibers is increased to prevent J o u r n a l P r e -p r o o f Journal Pre-proof anchorage of droplets [136] . Carbon-based and cellulose fibers nanomaterials can be used as a porous and breathable substitute to conventional PPE fibers [137] .

Reusability of kits and masks does not only save the cost but is also an environment-friendly approach to mitigate COVID-19. Recently, 'LIGC application limited' launched the anti-viral and reusable microporous graphene masks [138] . A hydrophobic and reusable nanoporous template was developed by El-Atab et al. [139] to reuse N95 masks with a replaceable filter membrane.

Sewage and wastewater can potentially act as a reservoir and an indirect transmitter of SARS-CoV-2. Mallapaty [140] postulated that mRNA content of SARS-CoV-2 in sewage and wastewater could predict the degree of severity of COVID-19 in that particular area. Nanotechnology can also help in combating the plastic pollution generated, which has become a massive problem after the onset of COVID-19 [145, 146] . The discarded PPE kits, The SARS-CoV-2 pandemic has alerted the humankind to push their limits and alarmed for better preparedness to deal with such pandemics. Nanotechnology, with its powerful armour can provide a range of tools which can be used in early detection and mitigation of any other future viral outbreak so that it could be stopped in time.

Though triune of nano-tools in detection, therapeutics, and protection and mitigation are a 'pandora box' of opportunities and latest technologies, they still have to overcome many J o u r n a l P r e -p r o o f Journal Pre-proof challenges to be developed as a reliable and robust tool to fight this pandemic. The major concerns and challenges associated with nano-tools are as follow:

Non-targeted nano-toxicity and safety of nanomaterials applications are the most critical concerns regarding their uses against COVID-19. Nanoparticles show geometry, surface and concentration-dependent toxicity and antimicrobial activities [81, 153] . Their bio-distribution pattern reveals that they tend to accumulate in the liver, kidneys, and brain via the circulatory system and affect the immune system [154] . Similarly, high doses of nano-polymers have shown neuronal cell death. COVID-warriors spraying nano-based disinfectants should be made aware of the associated health hazards, and precautionary measures should be taken. In the current scenario, where unknowns are maximum against SARS-CoV-2, use of a wrong particle or high concentration of a nanoparticle can lead to adverse effects creating panic and doubt over the whole nano-system.

The properties of nanoparticles are dependent on their shape and size [28] . Further, gaining public trust, solving ethical issues and adaptation to new technologies will not be easy. Siegrist et al. [158] in their study found that the public is more concerned about nanotechnology than experts and industry. The public perception and their trust is an essential pillar on which a successful technology can be founded. Scientific communities, industries and policymakers need to come together to cope-up this exceptional health crisis with unprecedented innovations gifted by nanotechnology.

The good 'nano-tools' have provided a ray of hope to combat the harmful nanoparticles Highlights  This review summarizes the nano-tools in detection, therapeutics and mitigation of SARS-CoV-2.  Multi-disciplinary approaches of nano-tools against COVID-19 with the economic, reliable, rapid and robust technologies are discussed.  Focus is provided on critical analysis of nano-tools before using this against COVID-19.

J o u r n a l P r e -p r o o f

Brief history of Pandemics (Pandemics Throughout History)

Lipid-based vaccine nanoparticles for induction of humoral immune responses against HIV-1 and SARS-CoV-2

Ivermectin: an award-winning drug with expected antiviral activity against COVID-19

Nanotechnology in early detection of cancer

Nanotechnology responses to COVID-19

Biomedical nanoparticle design: What we can learn from viruses

Nanomaterials and nanotechnology-associated innovations against viral infections with a focus on coronaviruses

A new coronavirus associated with human respiratory disease in China

Highly parallel direct RNA sequencing on an array of nanopores

Direct RNA nanopore sequencing of full-length coronavirus genomes provides novel insights into structural variants and enables modification analysis

Direct RNA sequencing and early evolution of SARS-CoV-2, bioRxiv

The architecture of SARS-CoV-2 transcriptome

Surface ultrastructure of SARS coronavirus revealed by atomic force microscopy

Discovery of a novel family of SARS-CoV protease inhibitors by J o u r n a l P r e -p r o o f virtual screening and 3D-QSAR studies

Antibodies at work in the time of SARS-CoV-2

Sustainable and fast saliva-based COVID-19 virus diagnosis kit using a novel GO-decorated Au/FBG sensor

An evidence based perspective on mRNA-SARS-CoV-2 vaccine development

Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial, The Lancet

Engineered drug delivery devices to address Global Health challenges

On the alert for cytokine storm: immunopathology in COVID-19

Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome

Biosensors for managing the COVID-19 cytokine storm: Challenges Ahead

Multiplex serum cytokine immunoassay using nanoplasmonic biosensor microarrays

High-throughput electrochemical microfluidic immunoarray for multiplexed detection of cancer biomarker proteins

Graphene oxide signal reporter based

Ultrasensitive detection of nucleic acids using deformed graphene channel field effect biosensors

Rapid and sensitive detection of anti-SARS-CoV-2 IgG using lanthanide-doped nanoparticles-based lateral flow immunoassay

Detection of severe acute respiratory syndrome (SARS) coronavirus nucleocapsid protein in human serum using a localized surface plasmon coupled fluorescence fiber-optic

Cellular level biocompatibility and biosafety of ZnO nanowires

Diagnosing lung cancer in exhaled breath using gold nanoparticles

Detection of chikungunya virus DNA using two-dimensional MoS 2 nanosheets based disposable biosensor

Tear glucose measurement by reflectance spectrum of a nanoparticle embedded contact lens

A rapid bioassay for single bacterial cell quantitation using bioconjugated nanoparticles

Direct observation of glucose fingerprint using in vivo Raman spectroscopy

Policy considerations for mobile biosensors

Facile and inexpensive fabrication of zinc oxide based bio-surfaces for C-reactive protein detection

Nanotechnology diagnostics for infectious diseases prevalent in developing countries

Convergence of quantum dot barcodes with microfluidics and signal processing for multiplexed high-throughput infectious disease diagnostics

Nanoparticle-based mobile biosensors for the rapid detection of sepsis biomarkers in whole blood

Development of a needle shaped microelectrode for electrochemical detection of the sepsis biomarker interleukin-6 (IL-6) in real time

Electrochemical aptamerbased sensors for improved therapeutic drug monitoring and high-precision

Biocompatible near-infrared quantum dots delivered to the skin by microneedle patches record vaccination

Magneticnanosensor-based virus and pathogen detection strategies before and during COVID-19

Imaging in the era of molecular oncology

Infrared nanospectroscopy and nanoimaging of individual cell membranes and microvesicles exposed to air

Red and near infrared persistent luminescence nano-probes for bioimaging and targeting applications

Ag2S quantum dot: a bright and biocompatible fluorescent nanoprobe in the second near-infrared window

Detection of norovirus virus-like particles using a surface plasmon resonance-assisted fluoroimmunosensor optimized for quantum dot fluorescent labels

Live cell imaging of single genomic loci with quantum dot-labeled TALEs

Viral nanoparticles as platforms for next-generation therapeutics and imaging devices

Viral nanoparticles for drug delivery, imaging, immunotherapy, and theranostic applications

encapsulating quantum dots into enveloped virus in living cells for tracking virus infection

Silver nanoclusters as fluorescent probes for selective and sensitive detection of copper ions

DNA-Ag nanoclusters as fluorescence probe for turn-on aptamer sensor of small molecules

Graphene oxide/nucleic-acidstabilized silver nanoclusters: functional hybrid materials for optical aptamer sensing and multiplexed analysis of pathogenic DNAs

Shuttle-based fluorogenic silver-cluster biolabels

Label-free time-and space-resolved exometabolite sampling of growing plant roots through nanoporous interfaces

Computational design of ACE2-based peptide inhibitors of SARS-CoV-2

Dendritic cell targeted chitosan nanoparticles for nasal DNA immunization against SARS CoV nucleocapsid protein

Severe acute respiratory syndrome coronavirus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptide

Preparation of virus-like particle mimetic nanovesicles displaying the S protein of Middle East respiratory syndrome coronavirus using insect cells

peptide inhibitor for Middle East Respiratory Syndrome Coronavirus

HTCC as a highly effective polymeric inhibitor of 2 SARS-CoV-2 and MERS-CoV 3 A

Toward nanotechnology-enabled approaches against the COVID-19 pandemic

Autophagy and SARS-CoV-2 infection: A possible smart targeting of the autophagy pathway

Nanotechnology-based antiviral therapeutics

Functional carbon quantum dots as medical countermeasures to human coronavirus

A facile inhibitor screening of SARS coronavirus N protein using nanoparticlebased RNA oligonucleotide

Enhanced cellular internalization: A bactericidal mechanism more relative to biogenic nanoparticles than chemical counterparts

An overview of severe acute respiratory syndrome−coronavirus (SARS-CoV) 3CL Protease inhibitors: Peptidomimetics and small molecule chemotherapy

Squalene-based multidrug

Calming cytokine storm in Pneumonia by targeted delivery of TPCA-1 using platelet-derived extracellular vesicles

Mesenchymal stem cells and management of COVID-19 pneumonia

Immunomodulatory nanodiamond aggregate-based platform for the treatment of Rheumatoid Arthritis

Cytokines as biomarkers of nanoparticle immunotoxicity

Photobiomodulation and antiviral photodynamic therapy as a possible novel approach in COVID-19 management

Trends and targets in antiviral phototherapy

Pneumonia treatment by photodynamic therapy with extracorporeal illumination -an experimental model

Monoclonal-Type" plastic antibodies for COVID-19 treatment: what is the idea?

A pharmacological perspective of chloroquine in SARS-CoV-2 infection: An old drug for the fight against a new coronavirus?

How can nanotechnology help to combat COVID-19? Opportunities and urgent need

Development of nanoparticle-delivery systems for antiviral agents: A review

Polymeric delivery systems for nucleic acid therapeutics: Approaching the clinic

Cellular Nanosponges Inhibit SARS-CoV-2 Infectivity

The inorganic polymer, polyphosphate, blocks binding of SARS-CoV-2 spike protein to ACE2 receptor at physiological concentrations

Poly(lactic-coglycolic acid) nanoparticle-mediated interleukin-12 delivery for the treatment of diabetic retinopathy

Therapeutic siRNA silencing in inflammatory monocytes in mice

Pulmonary delivery of nanostructured lipid carriers for effective repurposing of salinomycin as an antiviral agent

Synthetic peptides coupled to the surface of liposomes effectively induce SARS coronavirus-specific cytotoxic T lymphocytes and viral clearance in HLA-A*0201 transgenic mice

Impact of the surface functionalization on nanodiamond biocompatibility: A comprehensive view on human blood immune cells

Nanotheranostics against COVID-19: From multivalent to immunetargeted materials

Carbon Nanotubes for Targeted Drug Delivery

Novel coronavirus-like particles targeting cells lining the respiratory tract

Construction of SARS-CoV-2 virus-like particles by mammalian expression system

The optimized fabrication of a novel nanobubble for tumor imaging

Nanobubbles: a promising efficient tool for therapeutic delivery

Ozone therapy: A clinical review

Engineering protein nanocages as carriers for biomedical applications

Nanocaged platforms: modification, drug J o u r n a l P r e -p r o o f delivery and nanotoxicity. Opening synthetic cages to release the tiger

Ferritin nanocage-based methyltransferase SETD6 for COVID-19 therapy

Nano-microparticles as immune adjuvants: correlating particle sizes and the resultant immune responses

Targeting antigens to dendritic cell receptors for vaccine development

New non-oxide photocatalysts designed for overall water splitting under visible light

Bacterial inactivation and degradation of organic molecules by titanium dioxide supported on porous stainless-steel photocatalytic membranes

Photoinduced antiviral carbon nanohorns

Omics-based mechanistic insight into the role of bioengineered nanoparticles for biotic stress amelioration by modulating plant metabolic pathways

Coron aviru s-Nanot ech-Surfa ce-Sanit izes-Milan with-Nanom ateri als-Remai ning-Self-steri lized -for-Years

Efficient and quick inactivation of sars coronavirus and other microbes exposed to the surfaces of some metal catalysts

Curcuma longa aided

Ag/CS nanocomposite coating of surfaces as SARS-CoV-2 contamination minimizing measure towards containment of COVID-19: a Perspective

Modified cyclodextrins as broad-spectrum antivirals

Future antiviral surfaces: Lessons from COVID-19 pandemic

Innovative non-thermal plasma disinfection process inside sealed bags: Assessment of bactericidal and sporicidal effectiveness in regard to current sterilization norms

Plasma-activated water: An alternative disinfectant for S protein inactivation to prevent SARS-CoV-2 infection

Chick-Watson kinetics of virus inactivation with granular activated carbon modified with silver nanoparticles and/or copper oxide

Correspondence: Angiotensin-converting enzyme 2 coated nanoparticles containing respiratory masks, chewing gums and nasal filters may be used for protection against COVID-19

Protecting healthcare workers during COVID-19 pandemic with nanotechnology: A protocol for a new device from Egypt

Nanotechnology in textiles

Graphene modified multifunctional personal protective clothing

Nanotechnology-based disinfectants and sensors for SARS-CoV-2

Flexible nanoporous template for the design and development of reusable anti-COVID-19 hydrophobic face masks

How sewage could reveal true scale of coronavirus outbreak

Fate of COVID-19 occurrences in wastewater systems: emerging detection and treatment technologies-a review

Opportunities and challenges for biosensors and nanoscale analytical tools for pandemics: COVID-19

Increased plastic pollution due to COVID-19 pandemic: Challenges and recommendations

Microplastics in the environment: Occurrence, perils, and eradication

COVID-19 vaccine development and a potential nanomaterial path forward

Industry 4.0 technologies and their applications in fighting COVID-19 pandemic

The antimicrobial activity of nanoparticles: present situation and prospects for the future

Nanomaterials and nanoparticles: Sources and toxicity

Comparative study of leaching of silver nanoparticles from fabric and effective effluent treatment

Nanoparticles in the environment: where do we come from, where do we go to?

Stability of SARS-CoV-2 in different environmental conditions

Risks and nanotechnology: the public is more concerned than experts and industry

A novel receptor-binding domain (RBD)-based mRNA vaccine against SARS-CoV-2

Towards effective COVID-19 vaccines: Updates, perspectives and challenges

Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine induces equivalent preclinical antibody titers and viral neutralization to recovered COVID-19 patients

Development of an inactivated vaccine candidate for SARS-CoV-2

Nanobodies: prospects of expanding the gamut of neutralizing antibodies against the novel coronavirus, SARS-CoV-2

Arcturus-Reports-Additional-Supportive-Preclinical-Data-for-its-COVID-19-Vaccine-Candidate

A COVID-19 mRNA vaccine encoding SARS-CoV-2 virus-like particles induces a strong antiviral-like immune response in mice

Peptide nanoparticles as novel immunogens: design and analysis of a prototypic severe acute respiratory syndrome vaccine

Purified coronavirus spike protein nanoparticles induce coronavirus neutralizing antibodies in mice

Acknowledgements: SK thanks UGC, New Delhi for awarding her with JRF and SRF. MK