1 Introduction

1.1 Outbreak of nSARS-CoV2 and COVID19 pandemic

First-ever reported case of nSARS-CoV2 in December 2019 at Wuhan, China rapidly spread globally and resulted in a global pandemic [1]. There are several theories regarding virus origin however Bats are considered a prominent source of nSARS-CoV2. The virus is rapidly transmitted in the population via aerosol and formites modes and causes acute respiratory distress syndrome [2]. On January 30, 2020, World Health Organization (WHO) declared the outbreak a public health emergency of international concern. Later, WHO declared the spread of nSARS-CoV2 and the disease caused as COVID19 global pandemic on March 11, 2020 [3]. The infection with nSARS-CoV2 results in viral pneumonia where upper and lower respiratory tissue is more commonly affected named coronavirus disease 2019 (COVID19) [4]. Coronaviruses (CoVs) are classified based on crown-shaped spikes present on their surfaces and these CoVs are classified into four main genera namely, alpha-coronavirus (α-CoV), beta-coronavirus (β-CoV), gamma-coronavirus (γ-CoV), and delta-coronavirus (δ-CoV). Coronavirus belong to Coronaviridae family, Nidovirales order where beta coronavirus are more likely cause ARDS and COVID19 [5]. Earlier, two more coronavirus outbreaks were reported in the past where Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) in 2002–2004 and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in 2012–2014 belong to beta coronavirus [6].

Previous coronaviruses outbreaks including SARS-CoV and MERS-CoV represent positive-strand RNA viruses and show significant similarity with nSARS-CoV2 [7]. Beta Coronavirus genome 31 kb encodes spike protein (S-protein), an envelope protein (E-protein), membrane glycoprotein (M-protein), and Nucleocapsid protein (N-protein) [8]. Like other beta coronaviruses, nSARS-CoV2 infects the upper and lower respiratory tract via Angiotensin-Converting Enzyme 2 (ACE2). The receptor-binding domain (RBD) of nSARS-CoV2 differs from other previous coronaviruses i.e. SARS-CoV and MERS-CoV. Infection caused by nSARS-CoV2 trigger massive immune response both innate and adaptive [9]. The severe infection of nSARS-CoV2 triggers the release of interleukins-1β, 2, 6, 7, 8, and 10 (IL-1β, IL-2, IL-6, IL-7, IL-8, and IL-10), granulocyte-colony stimulating factor (GSF), tumor necrosis factor-α (TNF-α), interferon-γ, induced protein (IP-10), monocyte chemo attractant protein-1 (MCP-1) and macrophage inflammatory-protein 1-α (MIP-1α) [10, 11]. Effective clinical diagnosis of nSARS-CoV2 involves the use of antigen and real-time PCR-based tests however, diagnosis also involves X-Rays and CT scans. During the pandemic, several therapeutic were used clinically anti-inflammatory, antiviral, immune modulators, and plasma replacement therapy shown significant beneficial outcomes [12, 13].

2 COVID19 pandemic and nanotechnology

Outbreak of nSARS-CoV2 and COVID19 is novel and hence new approaches become inevitable to diagnose, sterilize, and find effective therapeutics and vaccines for the management of pandemic. Nanotechnology-based inventions including nano-designs, formulations, platforms for vaccines, and adjuvant for therapeutic had showed promising results in the fight against COVID 19 [14]. Nanotechnology-based inventions response was prompt and effective not only in the management of the COVID19 pandemic but also in the containment of the virus, proving mask and PPE to control virus spread and transmission. Nanotechnology-based inventions, formulations, and designs offer several advantages over conventional methods in the fight against the COVID 19 pandemic (Fig. 1) [15]. One and most promising advantage of Nanotechnology inventions is size and ease in functionalizing groups for desired properties. Using a nanotechnology-based platform where environmental sensing; air and water screening provide substantial data useful in the viral spread and dynamic of the pandemic [16].

Fig. 1
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Figure demonstrates the use of nanotechnology designs, inventions, and materials in the fight against the COVID19 pandemic

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2.1 Nanotechnology-based materials

Since the time of the outbreak of nSARS-CoV2 and COVID19 pandemic nanotechnology response was remarkable results in various products such as disinfectants, fabric with antiviral properties used for the design of personal protective types of equipment/gear (PPE) for medical and non-medical uses [17, 18]. Though the use of nanotechnology-based inventions/products is not limited to the development of PPE, technology played a pivotal role in diagnostic, therapeutic, and vaccine development [19]. Highly transmissible nSARS-CoV2 requires disinfectant and protective gear such as masks and PPE Kits to control the spread of the virus and control COVID19 [20]. Like most other infectious coronaviruses, nSARS-CoV2 also infects and transmits via aerosol droplets primarily however formites (surface contaminations) are another mode of transmission. The first step in fighting against virus spread and the COVID19 pandemic remain the dissemination of the virus present in the air and surface hence need for an effective disinfectant is inevitable [21]. There are two distinct approaches; one by the spray of functionalized nano-designs with antiviral properties on normal fabric and the second using nanomaterial with antiviral properties for fabric design to develop antiviral material to fight against COVID19 [22]. Earlier studies showed that Goldshield 5 used for spray-on surgical masks offers antibacterial protection specifically against gram-positive and gram-negative bacteria [23]. Goldshield 5 is first-generation approved material under US-FDA regulation as antibacterial coating material [24,25,26].

2.2 Nanotechnology-based materials in designing mask and PPE kits

GS75 is a modified material using a formulation of an organosilane water-stabilized quaternary ammonium chloride formulation in long alkyl chains consisting of a nonionic surfactant, a siloxane molecule that forms a non-polar covalent bond between the surfaces of masks and filters and that will cross-link to the inert materials [27]. The developed material used coating on PPE Kits and Mask for antiviral protection and was reported effective against nSARS-CoV2. The design of antiviral material also seeks metal ions such as Silver and Copper along with other coating materials including benzalkonium chloride, polymers, metal oxides, and functional nanomaterial [28]. The study also showed that the coating with GS75 material on the fabric used for masks and PPE kits provides antiviral protection for 3 days up to 50 °C and was reported safe as no severe toxicity was reported [29, 30]. Pemmada et al. and Imani et al. demonstrated nanotechnology materials used in coating masks, gowns, surgical drapes, textiles, high-touch surfaces, and other personal protective equipment [21, 22]. Similarly, Jung et al. developed and evaluated Copper-Coated Polypropylene Filter Face Mask for antiviral properties [31]. In this study, a commercial Korean Filter (KF) 94 respirator was treated with an oxygen ion beam followed by copper deposition resulting in a ready-to-use mask with the antiviral property (Table 1). Earlier, Sousa et al. demonstrated cupper coating provides antimicrobial and antiviral properties and can be used as coating material effectively [32, 33].

Table 1 Table summarizes nanotechnology-based material developed to design fabrics, coating for masks and PPE kits [31, 34]
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Takeda et al. developed and investigated Copper Iodide Nano-particles to inactivate nSARS-CoV2 in fabric via doped film design [34]. Cupper metal possesses virucidal properties and CuNPs extend virucidal properties at nano-scale ideal for fabric used for masks and PPE kits. Meister et al. developed and demonstrated nano-scale copper and silver film available for coating on fabric in the design of mask and PPE kits with antibacterial and antiviral properties [35]. In a recent study, Souri et al. designed and evaluated an antiviral formulation using nano-Cu conjugated with PLA for coating the mask for antiviral properties [36]. The developed formulation was used for 3D printing also reusable and hence environmentally friendly. In a recent study, Ha et al. investigated the antiviral activity of Cu-NPs where a high-energy electron beam was used to synthesize NPs [37]. The study showed energy induced Cu-NPs showed antiviral activity against the H1N1 influenza virus. Earlier, Gupta et al. reported the antiviral property of Copper NPs cold spray. The study also showed the effectiveness of CuNPs for enveloped viruses over non-enveloped viruses and hence such formulation might be effective against nSARS-CoV2 [38]. Based on experimental findings where nano-copper designs over conventional copper were reported effective in attenuating/killing viruses, CuNPs might be used for the coating to mask and PPE kits. Rabiee et al. studied antiviral activity against the H1N1 influenza virus of ZnO-NPs [39]. The study also report antioxidant, antibacterial and mammalian cell viability of ZnO-NPs where photo-catalytic and biomedical properties were promising.

Yüce and Filiztekin demonstrated the scope and potential of nanomaterial in developing cost effective and robust bioelectronics for the diagnosis of SARS-CoV2 [40]. Here several nano formulations were evaluated in-vitro plate forming units using IO-NPs and reported eight-fold reductions in virus titre. In a recent study, Sarkar et al. evaluated the antiviral potential of different nanoparticles gold nanoparticles, silver nanoparticles, quantum dots, carbon dots, graphene oxide nanoparticles, and zinc oxide nanoparticles [41]. Nanoparticles remain associated with cytotoxicity and emphasis has been given to synthesizing green NPs to combat toxicity. Additionally, surface functionalization is the key approach to minimizing/limiting cytotoxicity [42]. In the COVID19 pandemic, a massive volume of mask and PPE kits were used and are still being used hence green synthesis of NPs provides a sustainable and environment friendly [43]. In a recent study, Prasher and Sharma discussed self-sterilizing surfaces using nanotechnology designs [44]. Tang et al. examined the antiviral property of cationic nanosized cotton fibers ideal for mask and PPE Kit production [45]. The study also demonstrated the antiviral/biocidal activity of nanosized cotton fibers via reactive oxygen species (ROS) generation. Nanosized cotton fibers are associated with strong electrostatic interaction with anionic photosensitizes. These functionalized cotton nano-fibers synthesized using self-propagating 2-diethyl amino ethyl chloride conjugated with photosensitizes restrict microbial growth by 990% and are ideal for fabric used in mask and PPE.

2.3 Nanotechnology in virus detection

Since the time of the outbreak of nSARS-CoV2, detection and diagnosis of infection remain key challenges as it was a novel virus. Subsequently, diagnosis and viral detection become critical for COVID19 management, hence robust and point to care approaches were required [46]. Initially, clinical samples were diagnosed using molecular and immunological profiling where multiple parameters need to examine such as complete blood count (CBC), C Reactive protein level (CRP), lactose dehydrogenase (LDH), Aspartate aminotransferase (AST), alanine aminotransferase (ALT); AST/AL, pro-calcitonin, troponin I. Lymphopenia etc [47]. Simultaneously, imaging techniques such as chest X-Ray and CT were used to understand disease severity rather than infection. Real-time PCR-based diagnosis played a critical role in the early and effective diagnosis of nSARS-CoV2 infection. Immunological profiling precisely pro-inflammatory cytokines including interleukin-1β (IL-1β), IL-1RA, IL-2, IL-6, IL-7, IL-8 (CXCL8), IL-9, IL-10, IL-17, IL-18, tumor necrosis factor (TNF-α), interferon-gamma (IFN-gamma), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein 1 (MIP-1alpha/CCL3), monocyte chemo-attractant protein-1 (MCP-1/CCL2), interferon gamma-induced protein 10 (IP-10/CXCL10), and fibroblast growth factor (FGF) provide a scientific basis of infection and severity of COVID19 as well [48, 49]. Though these techniques are effective but remain associated with several limitations and false-positive results also. Additionally, nSARS-CoV2 and its variants are highly contagious and transmissible hence, a rapid point to care diagnosis was a key in the development of diagnostic kits and methods.

Nanotechnology-based molecular diagnostic approaches showed fast, rapid, and pathogen-specific detection in COVID19. Nanoparticles (NPs) are nanotechnology designs extensively used in nSARS-CoV2 diagnosis in COVID19 compared to other nano-designs. In a recent study, Tavakol et al. advocated the use of different types of NPs in the diagnosis and detection of nSARS-CoV2 [13]. It is evident, that antibody-based approaches and serology largely seek viral genome i.e. ss positive RNA strand where sensitivity, specificity, and accuracy remain a major concern. Xiang et al. demonstrated gold NPs conjugated with IgM/IgG immunoglobulin not only effectively detect viral RNA but also cut the downtime period required for sample collection and processing [13]. Cavalcanti and Nogueira demonstrated in their study rapid viral detection using gold NPs conjugated with IgM/IgG [50]. Another study uses a chiral AuNPs (CAu NPs)-quantum dot (QDs) nano-composite to result in an ultra-sensitive chiro-immunosensor for a large range of viruses including respiratory viral pathogens. The nanotechnology-based platform was also used in previous coronavirus outbreaks for early detection of the virus to develop robust diagnostic tools and kits (Table 2). Different nanoparticles including polymeric NPs, chaperone-mediated ferritin NPs, and spike protein conjugated NPs, self-assembling protein nanoparticles (SANPs), gold nanoparticles (AuNPs), Silver nanoparticles (AgNPs), lumazine synthase NPs and Self adjuvant nanoparticles (SANPs) evaluated for their role in viral detection [51,52,53,54,55,56,57,58,59,60,61,62,63,64,65].

Table 2 Table summarizes nanoparticles for the early and rapid detection of viruses including nSARS-CoV2 [64, 66]
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NPs have several advantages over other nano-designs first easy to synthesize, unique in size/dimension, and can accommodate a wide range of conjugating materials [66, 67]. In diagnostic development NPs provide instant detection as described by Moitra et al. using gold NPs based on colorimetric platform results in COVID19 detection in less than 10 min using RNA samples [68]. The study utilizes antisense oligonucleotides (ASOs) specific for N-gene (Nucleocapsid phosphoprotein) of SARS-CoV-2. For viral detection using different NPs two-approach becomes popular one using an optical platform and a second electrochemical. Kim et al. demonstrated a label-free spectrophotometry method for the detection of MERS-CoV in clinical samples. In the study, citrate-capped AuNPs conjugated with thiolated ssDNA probes were used for viral detection [69]. The developed method not only provides rapid viral detection but also allows a large surface area essential for accuracy. In addition to optical methods, electrochemical-based platforms utilize nucleic acid detection, and Lew et al. developed AuNPs-based detection methods not only provide rapid detection but also amplify the signal that helps in the detection of the virus even at low titer [70]. NPs offer a wide range of sample detection for the presence of viruses where samples from sputum, throat, swabs, urine, plasma, feces, oral swabs, whole blood, and saliva can be used effectively [71].

2.4 Nanotechnology-based materials in surface decontaminations

Spread and transmission of nSARS-CoV2 are primarily via aerosol and fomites. Chemical disinfectants precisely chlorides, peroxides, quaternary amines, and alcohols are used for surface disinfection and sterilization of surfaces and personal protective equipment [72]. Though the chemicals disinfectants for nSARS-CoV2 showed promising results in sterilizing surfaces and PPE however several limitations remain associated such as public health and environmental issues [19]. Additionally, the concentration of chemical disinfectants affects the efficacy and activity associated with short timed. Nanotechnology-based formulations were developed for viral sterilization and surface cleaning showed the promising result. Various nano-designs are used to develop disinfectant formulations using NPs; Gold, Silver, Copper, titanium dioxide, etc [73]. These nano-materials offer disinfectant activity against coronavirus via generating reactive oxygen species (ROS), generating photo-dynamic and photo-thermal capabilities [74]. It is evident NPs and other nano-designs are cytotoxic and hence biodegradable nanomaterials such as polymeric lipid-based formulation. Querido et al. developed and evaluated self disinfecting nanoformulation to control infections including nASRS-CoV2 [75]. Vaze et al. explained mechanism of air utilizing engineering water nanostructures based on nano-sanitizers (Table 3) [76].

Table 3 Table summarizes nanotechnology-based formulations and inventions for virus sterilization and surface decontamination [41, 74]
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2.5 Nanotechnology-based vaccine against COVID19

In early 2020 after the nSARS-CoV2 genome sequencing vaccine design was started where several platforms such as protein, Micro RNA molecules, whole virus, and nucleic acid were used. As a result in late 2020 vaccine become available for clinical use (emergency uses). Vaccines elicit both antibody (humoral)-mediated immunity (AMI) and cell-mediated immunity (CMI), long-lived immune responses, and immune memory. Vaccines are associated with premature degradation of light/heavy chain subunits and non-specific delivery reduces efficacy. Silva et al. studied the role of nano-designs and formulations not only to improve the stability of vaccine subunits but also to target delivery [77]. The use of nanotechnology in vaccine development is not new and earlier several vaccine prototypes were developed for viruses such as hepatitis, H1N1 influenza, and coronaviruses as well. Previously Li et al. investigated antigen delivery against the hepatitis B virus using HBsAg-functionalized solid lipid nanoparticles (SLNs) [78]. The result demonstrated a strong immune response including cell-mediated and antigen mediated with HBsAg functionalized solid lipid nanoparticles. The study also reports a higher cellular update and minimal cellular toxicity with HBs-Ag SLNPs. Nanotechnology-based formulation/inventions are also used as the carrier for immunogenic molecules where targeted delivery remains a key concern (Fig. 2). Several findings demonstrated the use of poly lactic-co-glycolic acid (PLGA), polymeric NPs, and calcium phosphate as cargo for immunogenic molecule delivery [79]. Study has showed polyethyleneimine nanoparticles conjugated with spike protein of SARS-CoV showed enhanced immune response in the animal model [80]. Zhao et al. formulated a vaccine candidate (ARCoV) based on a lipid-nanoparticles-encapsulated mRNA (mRNA-LNP) encoding the receptor-binding domain (RBD) of SARS-CoV-2, leading to Th1-biased cellular responses and production of effective neutralizing antibodies against SARS-CoV-2 as shown in mice and non-human primates [55]. A detail of the vaccine designed against nSARS-CoV2 using nanotechnology is summarized in Table 4.

Fig. 2
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The figure demonstrates the applications of nanotechnology and nanotechnology inventions/designs in the fight against the COVID19; diagnosis, prevention, treatment and surveillance

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Table 4 Table summarizes nanotechnology-based formulations and inventions for vaccine design and development [30, 70, 81]
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2.6 Nanotechnology-based therapeutics to combat COVID19

The application is nanotechnology is vast and in the COVID19 pandemic nanotechnology designs, formulations and inventions become part of the drug development process to combat disease [82, 83]. These formulations/designs are being used for two major objectives one as the carrier for drug delivery and the second as therapeutic (Fig. 2). Nano-designs easily penetrate respiratory epithelia and precisely NPs due to nanoscale size and ease in functionalization offer a wide range of physicochemical properties. Indeed, nanotechnology-based cargoes are ideal for targeted drug delivery however in the COVID19 pandemic another avenue of nanotechnology was explored i.e. therapeutic [84]. Nanotechnology remains associated with novel drug development against nSARS-CoV2 and evaluation of repurposing therapeutic as well. Loczechin et al. investigated the therapeutic potential of functionalized carbon quantum dots (CQDs) against human coronaviruses [83]. The mechanism proposed that CQDs restrict the entry of HCoV-229E due to the functional group attached to CQDs. The study also reported CQDs to inhibit viral replication and reduce titer volume significantly. Huang et al. investigated MERS-CoV inactivation using gold nanorods (AuNRs) where a series of heptad repeat 1 (HR1) peptide inhibitors restrict the entry of MERS-CoV2 to the host cell. Several findings have demonstrated that nSARS-CoV2 and ACEII receptor require a conformational change for viral entry into the host cell [81]. Abo-zeid et al. demonstrated that Fe2O3 NPs strongly interacts with S1-RBD of the SARS-CoV-2 and restrict viral entry to the host cell significantly [85].

Key therapeutics that remains associated with the treatment of COVID19 includes IFN-α, Lopinavir/ritonavir, Ribavirin, Chloroquine phosphate, and Arbidol. Additionally, Kaletra (Lopinavir/Ritonavir), hydroxychloroquine, oseltamivir phosphate, and Azithromycin have shown promising results as antiviral/anti-inflammatory agents against nSARS-CoV2. PegIntron® and Pegasys® are two FDA-approved NPs containing PEG-interferon alfa 2b and PEG-interferon 2a for the treatment of COVID19 [86]. Additionally, Chitosan NPs were used for INFα conjugated with Lopinavir/ritonavir were used for the management of COVID19. Another finding demonstrated that Glutathione-capped Ag2S nano-clusters were also potent nanomaterial for coronavirus suppressing. Ag NPs absorb the –SH groups of viral proteins and could serve as an effective therapeutic against nSARS-CoV2 [87]. Similarly, the study demonstrated a strong antiviral activity of graphene oxide (GO) with Ag NPs study against Feline coronavirus (FCoV). There is a grown list of nano-formulations (Table 5) that are being used/under trial for the treatment of COVID19 and or serving as a carrier for therapeutic including polymeric NPs, chaperone-mediated ferritin nanoparticles, Nano-bodies, Self-Assembling Protein Nanoparticles (SAPN), an adenoviral vector encoding Ad5, spike protein nanoparticles, VLPs, AuNPs, AgNPs, and Lumazine synthase NPs [81, 88].

Table 5 Table summarizes nanotechnology-based formulations and inventions for therapeutic development against nSARS-CoV2 and COVID19 [83, 84]
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3 Challenges and prospects

The key challenge with nanotechnology-based inventions and formulations intended for clinical uses is toxicity. Further surface functionalization often opted to reduce toxicity however difficult to remove. Another major challenge that remains associated with the use of nanotechnology is the non-availability of pretested formulations as novel SARS-CoV is new and diagnosis, detection, surveillance, therapeutic and vaccine uses need extensive preclinical and clinical studies to profile safety and efficacy profile. On several occasions, these nanotechnology-based inventions and formulations seem effective in animal models but fail when evaluated in the clinical setting. Nanotechnology-based formulations in the management of the COVID19 pandemic are still evolving and changing the genomic structure of nSARS-CoV2 continuously posing limitations on the effectiveness of the technology. In the last two years with the COVID19 pandemic and previously evaluated nano-formulations with other coronaviruses SARS-CoV and MERS-CoV along with influenza H1N1 and hepatitis showed a promising future in a wide range of applications including diagnosis and detection, design of biosensor for surveillance and monitoring, antiviral fabric and coating to mask and PPE, development of novel therapeutic and repurposing of existing therapeutic and vaccine development. Sterilization, surface decontamination, sanitization of skin, etc. pumped/released tonnes of the chemical into the environment does have serious complications to human health and the environment. Hence a sustainable approach remains the utmost priority where nano-formulation with reuses and self-degradation capabilities are required. Certainly, nanotechnology-based inventions/formulations and designs are superior in many aspects to conventional approaches, and in the future, more effective and robust materials will be available to fight against infection.

4 Conclusion

The outbreak of nSARS-CoV2 in December 2019 tuned in the global pandemic COVID19 affected the lives of millions of people worldwide and is still underway. The fight against COVID19 and the spread of nSARS-CoV 2 and its variants are multidimensional where the diagnosis of new cases, surveillance of the environment (air and water), development of robust and rapid diagnostic kits, therapeutic and vaccine do require integration of modern technology. Nanotechnology-based formulations, designs, and inventions had shown promising results in the fight against nSARS-CoV2 (causative agent) and COVID19 (disease). The last two yeast nanotechnology-based formulations/inventions/designs fulfilled the critical need for the designing of efficient vaccines to prevent virus infection, early and fast diagnosis by the high sensitivity and selectivity diagnostic kits, and effective antiviral and protective therapeutics to decline and eliminate the viral load and side effects derived from tissue damages. Nanotechnology response in the COVID19 pandemic was outstanding including new diagnostic methods/tools, antiviral nano-formulation, coated fabric for mask and PPE, new drug development along with repurposing and vaccine development. Nanotechnology not only fulfills current requirements to fight against COVID19 pandemic but also offers a sustainable and environmentally friendly technology. Though there are a few limitations with nanotechnology-based products such as cytotoxicity and these limitations are being addressed via functionalization of nano-designs and formulation. Modern medicine coupled with nanotechnology provides a wide range of application and fight against not only nSARS-CoV2 but also other viral/microbial pathogens.