Review Article | Open Access
Vahid Alimardani, Samira Sadat Abolmaali, Ali Mohammad Tamaddon, "Recent Advances on Nanotechnology-Based Strategies for Prevention, Diagnosis, and Treatment of Coronavirus Infections", Journal of Nanomaterials, vol. 2021, Article ID 9495126, 20 pages, 2021. https://doi.org/10.1155/2021/9495126
Recent Advances on Nanotechnology-Based Strategies for Prevention, Diagnosis, and Treatment of Coronavirus Infections
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is exponentially spreading across the world, leading to an outbreak of serious viral pneumonia. Antiviral therapies using chloroquine, hydroxychloroquine, and favipiravir have been approved by several countries to increase the quality of life of SARS-CoV-2-infected patients. Currently, several companies are intensively working on the production of coronavirus (CoV) vaccines, resulting in some specific vaccines that have been approved for CoV infections in humans. Nevertheless, efficient and specific prevention, treatment, and diagnosis are urgently required to combat the biological diversity and rapid mutation in CoV infections. Recently, significant attention has devoted to nanoformulation or nanoparticles (NPs) due to their specific features like high surface-to-volume ratio, drug encapsulation abilities, and specific optical properties to remove the complications of applied conventional therapeutic and diagnosis options. In this regard, NPs are increasingly used as new anti-CoV agents, vaccine carriers or adjuvants, and nanoscale biorecognition elements. The present review article provides a comprehensive discussion on the recent updates regarding the prevention, diagnosis, and treatment of different CoV infections with an emphasis on the application of NPs in vaccination, treatment, and diagnosis of CoV infections.
Infections with coronaviruses (CoVs) have been on top of the list of leading mortality causes in recent decades. In late 2019, a pandemic outbreak of a new CoV infection in humans, known as severe acute respiratory syndrome CoV-2 (SARSCoV-2) or COVID-19, has caused public anxiety . Current antiviral therapies are fairly effective in the treatment of CoV infections [2, 3]. To date, some countries have approved some antiviral drugs as pharmacological treatment options for COVID-19. However, some approved COVID-19-specific vaccines are available. Several companies have developed various vaccine candidates for human CoV (HCoV) infections which are in the clinical trial stage . Similar to other conventional therapeutic and diagnostic systems, CoV therapies and diagnostic systems also suffer from limitations in their efficient use in clinical situations to prevent, treat, and diagnose infections. The toxicity of antiviral drugs, low physicochemical stability of therapeutic agents, poor pharmacokinetics and bioavailability, low sensitivity, and high-cost and time-consuming methods have hindered the advance of novel formulations .
The nanotechnology-based formulations are the promising developing formulations which are benefited from eminent features such as high surface to volume ratio, easy surface modification, enhanced physicochemical stability, specific optical properties, and targeted and controlled release capabilities that can lead to lower toxicity and higher efficacy, making them more favorable for the effective prevention, treatment, and diagnosis of viral infections, especially CoV infections . Currently, different nanoparticle-based antiviral agents (especially gold and polymeric NPs) have drawn the attention of scientists due to their specific optical and encapsulation properties for prevention, diagnosis, and treatment of various viral diseases like Ebola, influenza, HSV, and HIV [7–12]. Given the extensive abilities of nanotechnology, it is probable that novelties in this field could substantially influence the advances in combat against CoV-associated infections. In context, the current review is focused on the potential use of nanotechnology for the prevention, diagnosis, and treatment of CoV infections. However, most of these studies are at primary steps but their outcomes are promising.
CoVs are mostly spherically shaped viruses with a diameter of around 60-140 nm. They contain a single-stranded positive-sense RNA genome as one of the largest genomes among RNA viruses . CoVs are split into four separate generations including α-, β-, γ-, and δ-CoV . α- and β-CoVs only infect mammals, while γ- and δ-CoVs can infect birds and some mammals. To date, seven CoVs such as CoV-OC43, CoV-229E, HCoV-OC43, CoV-HKU1, CoV-NL63, Middle East respiratory syndrome (MERS)-CoV, and severe acute respiratory syndrome (SARS)-CoV and SARS-CoV-2 or COVID-19 have been reported to cause infections in human [15, 16]. COVID-19 can result in severe upper respiratory infections similar to a common cold which can mostly lead to death in older people, mainly those with severe underlying health conditions compared to younger ones [17, 18]. The enveloped RNA genomes of CoVs encode three membrane proteins and nucleocapsid (N) protein associated with the RNA genome . The membrane proteins consist of the large spike (S) glycoprotein which contains the receptor-binding domain (RBD) that has a significant role in receptor binding and virus entrance to cells. Since the M protein of SARS-CoV can induce neutralizing antibodies and N protein has T cell epitopes, they have attracted significant attention for vaccine developments [20–22].
3. Conventional Prevention, Diagnosis, and Treatment of Coronavirus Infections
Combating viral infection is an enormous challenge in healthcare systems, primarily due to the challenges associated with the spread of viral infections as well as the potential capability of the virus to survive through mutations . Currently, the US Food and Drug Administration (FDA) and the National Medical Products Administration of several countries have approved limited emergency use of antiviral drugs as a remedy for COVID-19 . As can be seen in Table 1, many companies and institutes all over the world are working to develop HCoV vaccines. However, some approved specific vaccine treatments have been licensed for COVID-19, yet prevention measures (e.g., blocking the transmission routes such as the mouth and nose by a napkin, frequent washing of hands, and hand disinfection after presence in public places) are important strategies to combat CoVs. Besides, public transport, as well as eating or touching animals in places struggling with epidemics, should be avoided. Moreover, people should boost their immune system by the well-adjusted diet, sufficient exercise and rest, and maintaining their emotional and mental health. Patients should be isolated in specified hospitals and receive supportive treatments including bed rest, oxygen, calorie, and enough electrolytes in combination with drug treatments [16, 25]. The potential roles of nanotechnology in the prevention of CoV infections will be discussed in the succeeding sections.
NCT: National Clinical Trial; ChiCTR: Chinese Clinical Trial Register.
On the other hand, given that the medication in the early stages of infection is closely linked to the effectiveness or success of treatment for CoV infections and the challenges in CoV infections detection from clinical symptoms, the production of rapid detection systems can significantly reduce the spread and morbidity of these infectious species . Up to now, various diagnostic assays including protein microarray , enzyme-linked immunosorbent (ELISA), immunofluorescence , reverse transcription loop-mediated isothermal amplification (RT-LAMP) , and viral flow cytometry (FCM)  have been applied for fast and accurate diagnosis of coronavirus infections. Nevertheless, the determination of the genome sequences of coronaviruses, e.g., COVID-19, leads to the recognition of reverse transcription-polymerase chain reaction (RT-PCR) assays as a standard and highly sensitive technique for clinical diagnosis of COVID-19. The development of facile and quick assays is still a vital necessity [30, 31]. Since the RT-PCR method requires complicated machines, well-educated experts in molecular diagnostics, and specific laboratories, diagnostic kits have been designed by various research groups and companies to eliminate the RNA extraction and purification steps, resulting in rapid detection of CoV infections.
Currently, a broad range of pharmacological strategies, such as antivirals, and corticosteroid therapy, cell-based therapeutic options, and traditional Chinese medicine (TCM) have been applied to treat various CoV infections, as presented in Table 2. Recent antiretroviral therapy using HIV drugs has attracted increasing attention. Lopinavir/ritonavir, an HIV protease inhibitor, alone or in combination with other antiviral drugs or IFNα can contribute to the treatment of severe SARS-CoV or MERS-CoV patients [32–34]. IFNα promotes the immune responses of infected patients and also interferes with virus replication [35, 36]. In addition to protease inhibitors, nucleoside analogs have shown significant potentials for CoV infection therapy. For example, ribavirin or tribavirin can be used in the treatment of SARS-CoV and MERS-CoV infections by preventing inosine monophosphate dehydrogenase activity, which can prevent the guanosine triphosphate (GTP) synthesis required for RNA and DNA replication of virus [37, 38]. Another nucleoside analog, favipiravir, which has also shown anti-SARS-CoV-2 activity, is the first approved coronavirus drug in China’s National Medical Products Administration . The in vivo and in vitro anti-SARS and MERS activity of remdesivir, an Ebola drug, indicated that it can be used as a promising candidate for COVID-19 treatment . Oseltamivir has been used for COVID-19 patients, but its efficacy should be further evaluated . Altogether, despite the relative success of antiviral therapies in the treatment of CoV infections (especially in COVID-19), there are some concerns associated with their coadministration with other drugs as well as their potential side effects such as anemia, diarrhea, vomiting, and liver problems .
As pharmacological options, some medications used for the treatment of other diseases (e.g., malaria and arthritis) have recently gained increasing attention. Chloroquine and hydroxychloroquine have shown anti-SARS-CoV-2 activities and were recently approved by the FDA for limited emergency use against COVID-19 . In fact, they inhibit the virus entry into the cells and hence blocking its transport into the cell organelles . As another class of pharmacological options for treatment of CoV infections, corticosteroids have been applied to suppress cytokine production in SARS-CoV and MERS-CoV patients; nevertheless, there is no compelling evidence for its effectivity on COVID-19 treatment and some recommended its use for a short time [16, 44, 45].
According to Tables 1 and 2, in addition to the abovementioned therapeutic options, cell-mediated therapy based on immune and stem cell has been investigated as a promising option for the treatment of CoV infections. The convalescent plasma of the cured patients contains antiviral antibodies and can be exploited to reduce viral loading and mortality of patients [46, 47]. To date, in cell-based therapy of CoV infections, natural killer (NK) cells and mesenchymal stem cells (MSCs) have shown bright potentials in the treatment of COVID-19 infection. NK cells can lyse antibody-coated virus-infected cells by mediating antibody-dependent cellular cytotoxicity (ADCC) against SARS-CoV [48, 49]. MSCs can improve the cytokine storm syndromes, acute respiratory distress syndrome, and lung injury by suppressing the infiltration of immune cells to pulmonary tissues and proinflammatory cytokine secretion which can be a valuable treatment to inhibit the COVID-19-associated lung damage [50, 51]. Also, TCM has been used as a complementary therapy for CoV-infected patients, declining the side effects of conventional therapeutics. TCM herb formulae can be used to inhibit the activity of CoV infections via different mechanisms especially inhibition of the enzymatic activities and cellular entry. Based on Table 1, several TCM formulations are now available in clinical trials . Lately, in order to address the drawbacks of conventional prevention, diagnosis, and treatment of coronaviruses infections, the research community turned to nanotechnology to implement a new efficient nanotechnology-based approach to combat infections with coronaviruses which will be addressed in the next sections.
4. Nanotechnology in Coronavirus Infections
Nanotechnology is referring to design, synthesis, and application of materials with at least nanoscale size (<100 nm) in one dimension. Owing to small size, large surface area, and high loading capacities, as well as specific optical properties of NPs, they have been widely explored in a variety of biological systems to attain the intended therapeutic or diagnostic performance [116–120]. Currently, a variety of NPs have been explored as nanopharmaceuticals, or nanosized pharmaceuticals, for prevention and treatment of various human diseases such as viral infections. Most of approved nanoproducts in market have revealed lower toxicities and higher therapeutic efficacy compared to conventional formulations. Nonetheless, nanoformulations currently in clinical trials have demonstrated positive outcomes; thus, they are likely to be approved by the regulators in preceding years [121, 122]. Today, one important application in response to the increasing prevalence of viral infections especially coronavirus infections is the development of improved antiviral products. NPs applied in prevention, detection, and treatment of CoV infections are illustrated in Figure 1. Table 3 summarizes the description, pros and cons, and potential roles of NPs in coronavirus infections. In the next section, the application of NPs in prevention, diagnosis, and treatment of CoVs will be discussed.
4.1. Nanotechnology in the Prevention of Coronavirus Infections
The recent outbreak of CoV infection in the absence of effective conventional treatments highlights the importance of prevention and control of CoV transmission. Advances in nanotechnology have led to the development of nanotechnology-based vaccines, masks, and disinfectants for controlling CoV infections which are presented in the next sections.
4.2. Nanotechnology-Based Vaccines for Coronavirus Infections
Nowadays, vaccination has gained increasing attention owing to its promising results to combat various infections and to reduce the costs as well as deaths worldwide . The recent rapid emergence of CoV infection has shown that vaccination can act as a significant function in managing the social safety and public health. Coronavirus vaccination may either preserve people against infection or have a therapeutic impact. However, development of CoV vaccines has encountered some limitations including inadequate protectivity, the absence of high-throughput animal models, scale-up and GMP production, and safety concerns. There are currently different types of vaccine formulations including attenuated viruses, viral proteins (subunits or virus-like particles), nucleic acids, or recombinant viral vectors that have been used to target diverse CoVs [19, 129, 130]. Nevertheless, they have been significantly correlated with the risk of the weak immune response, reversion to pathogenic virulence, and inadequate immunogenicity and induced partial protection. Hence, while improving safety and efficiency of candidate vaccines, alternative options should be considered in vaccine development to shorten the access time. Nowadays, nanotechnology-based vaccination systems have shown promising potentials in resolving the limitations of conventional vaccine formulations. They have several capabilities such as (i) delivery of different types of vaccines; (ii) vaccine administration through nasal or oral routes to stimulate mucosal immune reactions; (iii) targeted and controlled release of single or multiple antigens to antigen-presenting cells, leading to prolonged half-life and antigen presentation to the immune cells; (iv) boosted immunogenicity of vaccines and adjuvants; (v) decline in the potential antigen toxicity; (vi) protection of the encapsulated antigens under harsh conditions; and (vii) stimulation of the immune response as adjuvants [131, 132]. Such findings and observations have inspired material scientists to imitate viral infection for production of nanotechnology-based vaccination systems. Design of CoV vaccines adopts various strategies; however, most of them target the structural proteins including S or spike, N, envelope (E), and membrane (M) proteins that they might act as the most important inducers of neutralizing antibodies . Following the identification of the SARS-CoV-2 structural proteins and promising results in development of the synthetic virus-like NPs [133, 134], Chen and coworkers recently developed a synthetic virus-like particle (sVLP) based on spontaneous protein corona formation using AuNPs and an avian CoV spike protein for vaccination in IBV-CoV infection, as presented in Figure 2 . Developed sVLP formulation led to efficient lymphatic antigen delivery, stronger antibody titers, increased splenic T cell response, and reduced infection-associated symptoms in an avian model of CoV infection in comparison to vaccination with free proteins. Moreover, in comparison with a commercial whole inactivated virus vaccine, sVLPs offered superior antiviral protection. In addition to AuNPs, polymeric NPs have been recently applied as sVLPs for promoting immune cell engagement and antigen processing against CoV infections. For instance, Tasca and coworkers developed a viral capsid-like hollow poly(lactic-co-glycolic acid) (PLGA) NP for entrapment of cyclic diguanylate monophosphate (cdGMP), a canonical stimulator of interferon genes (STING) agonist. The cdGMP upregulates the proinflammatory cytokines to shape the adaptive immunity, as an adjuvant, and recombinant MERS-CoV RBD antigens as Th1 immune responses and cellular immunity promoters against the MERS-CoV infectious. The developed formulation showed significant antigen-specific cellular and humoral responses in immunized mice .
In addition to synthetic NPs, MERS-CoV spike protein NPs have been employed against MERS-CoV infection. In this strategy, MERS-CoV S protein NPs are combined with an appropriate adjuvant to promote sufficient immunization against CoV infections. Coleman et al. showed the applicability of MERS-CoV S protein NPs to prompt a robust neutralizing antibody response to MERS-CoV . Following the mentioned research, they developed a formulation using MERS-CoV spike protein NPs and Matrix-M1 adjuvant to protect mice against MERS-CoV infection . Their results indicated that adjuvant combination with MERS-CoV S protein NPs can neutralize antibody response in vaccinated mice as well as providing efficient MERS-CoV replication blocking in the lungs. Furthermore, Jung et al. developed vaccination formulation based on recombinant adenovirus serotype 5 delivering the MERS-CoV S protein gene (Ad5/MERS) and MERS S protein NPs with alum adjuvant to induce cellular and humoral immune responses with heterologous prime-boost vaccination strategy . Results showed not only Ad5/MERS-induced-specific immunoglobulin G but also MERS S protein NP-induced-specific IgG. The results also revealed that just heterologous prime-boost immunization and homologous immunization with S protein NPs can induce MERS-CoV- neutralizing antibodies. Additionally, Ad5/MERS can induce Th1 cell activation, alone or in combination with S protein NPs. However, heterologous prime-boost vaccination Ad5/MERS regimens caused Th1 and Th2 responses, while homologous prime-boost vaccination did not exhibit any Th1 and Th2 responses indicating more usefulness of heterologous prime-boost for long-lasting immune responses against MERS-CoV. NPs could be also employed as adjuvants to prevent CoV infections. NPs have been administrated in combination with antigens as an adjuvant to enhance the immunization of vaccine systems. Sekimukai and colleagues developed two types of vaccine adjuvants based on AuNPs and Toll-like receptor (TLR) agonists to increase the efficacy of intranasally administrated ultraviolet- (UV-) inactivated SARS-CoV vaccine . Surface adsorbed recombinant CoV S protein AuNPs showed antigen-specific IgG response; however, it was unsuccessful to make a protective antibody and eosinophilic infiltration in the lungs in comparison to TLR agonists which effectively reduced the required extent of recombinant S protein for the vaccination and eosinophilic infiltration in the lungs after the SARS-CoV infection. Today, concerning the importance of CoV S protein in CoV vaccine development, Novavax, an American vaccine development company, has developed several recombinant NP-based vaccine candidates to target surface S protein of MERS infection which are in animal models’ testing stage . The surface ligands of COVID-19 have also attracted the attention of NanoViricides company to develop a nanoformulation based on nanoviricide® technology . In nanoviricides, polymeric micelles comprise a single-chain polymer conjugated to specific ligands that help in engulfing or coating the virus, resulting in virus neutralization and destabilization and may be viral genome attacking .
Currently, numerous antigens or adjuvants have been loaded into NPs to target antigen-presenting cells (APCs) resulting in efficient antigen recognition and presentation [142, 143]. Raghuwanshi and coworkers encapsulated plasmid DNA-encoding N protein (pVAXN) of SARS-CoV into biotinylated chitosan NPs for nasal immunization . Biotinylated chitosan NPs were surface-functionalized with a recombinant bifunctional fusion protein (bfFp) which contains a single-chain variable fragment (scFv) to target DEC 205 receptors of DCs. The positively charged chitosan NPs can efficiently bind to negative sialic residues in the nasal mucus. The slow release of the formulation as well as the transient opening of the tight junctions can enhance paracellular transport across the nasal mucosa. Moreover, the binding of receptor-specific ligands to chitosan microspheres enables receptor-mediated endocytosis leading to cell-specific delivery vaccine formulations [145, 146]. The polymeric nanoformulation vaccines are resistant to DNAse; thus, they can act as an in vivo efficient vaccination system. Intranasal administration of targeted polymeric nanoformulation in combination with anti-CD40 DC maturation stimuli can enhance the mucosal IgA and systemic content of IgG against N protein of SARS-CoV; however, no mucosal and systemic immune responses were observed for bare pDNA. Furthermore, results indicated higher systemic IgG responses for intramuscular injection of bare pVAXN or NP-loaded pVAXN as compared with the intranasal administration. Such a difference could be due to the low dosage of bare or nanoencapsulated DNA. In a study, Sun et al. showed that intramuscular administration of chitosan-encapsulated N protein of bovine CoV (BCV N) NPs can significantly enhance IgA and IgG levels as compared to Montanide ISA 206, an oil adjuvant, effectiveness of chitosan NPs to be used as an adjuvant for BCV N protein . Altogether, nanotechnology-based vaccine formulations are promising immune cell activators and antigen carriers for vaccination, but further studies are still required.
4.3. Nanotechnology in Prevention of Coronavirus Infections
As previously mentioned in Section 3, blocking transmission routes especially the mouth and nose is an important strategy to combat CoVs. Hence, efficient personal protection devices against CoV nanoscale aerosols have attracted increasing attention. However, N95 and N98 masks protect people against aerosols with 300 nm, smaller aerosols, and airborne viruses might be transmitted to the respiratory system, resulting in infection. Concerning the nanoscale size of CoVs, many research groups are focused on the production of nanofilter masks to prevent the transmission of CoV aerosols smaller than 300 nm. Recently, Leung and Sun have designed a nanofiber filter based on a single or multiple layers of electrostatically charged polyvinylidene fluoride (PVDF) nanofibers (with size ranges of 84, 191, 349, and 525 nm) deposited on a mat substrate to capture airborne COVID-19 and nanoaerosols with less than 300 nm . Results indicated that smaller nanofibers (84 nm) can offer higher mechanical capturing of neutral sodium chloride aerosols used as a virus model, which can be assigned to their large specific surface. In comparison to single-layer filters based on small nanofibers, small and large multilayer nanofiber filters were capable of capturing 90% of simulated 100 nm in size airborne COVID-19 which might be more hopeful for viruses with negative charges. In another research, they have developed a charged PVDF multilayer nanofiber filter to filter the simulated airborne COVID-19 using ambient nanoaerosols. Their results showed 6-layer charged nanofiber filter could be used to filter the nanoaerosols sizes of 50, 100, and 300 nm ambient aerosols with 88%, 88%, and 96% capture efficiency while the filtering efficiencies of 92%, 94%, and 98% could be achieved for the sodium chloride aerosols with the same size order . Recently, a Korea Advanced Institute of Science and Technology developed a washable and ethanol-sterilizable nanofiber-based filter that can be easily fitted inside a conventional mask to filter 94% of contaminants .
4.4. Nanotechnology-Based Surface Disinfectant in Coronavirus Infections
As another exposure-reducing strategy toward CoVs and concerning the importance of the contaminated surfaces in the spread of the CoVs, specific attention has also paid to decontamination of surfaces using 70–85% ethanol, NaClO, and iodine-based disinfectants . On the other hand, findings have approved the antiviral activity of NPs, resulting in their usage as surface disinfectants with cell membrane entrance virus replication inhibition as well as surface attachment interfere of the virus into cells . Therefore, the Nanotech Surface Company has recently developed a self-sterilizing formulation based on titanium dioxide and silver ions to disinfect buildings in Milan . Taken together, nanotechnology-based filters (face masks) and disinfectants are promising products for personal and public protections against CoVs which require further research.
4.5. Nanotechnology in the Diagnosis of Coronavirus Infections
Rapid and precise detection technique can reduce the spread and morbidity of CoV infections. There are numerous techniques being employed for the detection of CoV infections; however, most of them suffer from some limitations including low sensitivity, time-consuming procedures, high costs, and late detection . The current standard technique for CoV detection, RT-PCR, is a highly time-consuming technique requiring expert users, and complex devices, highlighting the need for sensitive and early detection of CoV infection. Novel detection assays based on nanotechnology have gained increasing attention. The unique properties of NPs such as their high surface area, easy functionalization, and special optical properties have led to their application as rapid, sensitive, and cost-effective diagnostic systems with less sample volume and laboratory equipment [155, 156]. During the last decades, a great deal of effort has been dedicated to the use of NPs in the design of various nanobiosensors for the detection of infectious diseases . In this section, different applications of NPs in design of colorimetric, optical, and electrochemical sensors for detection of CoV infections are presented.
4.6. Nanotechnology in Colorimetric Detection of Coronavirus Infections
Colorimetric biosensors are sensitive, selective, and low-cost detection tools capable of detecting analytes based on color changes that can be easily recognized by naked eyes or simple portable optical detectors [157–159]. Special physicochemical properties of NPs have led to emergence of new colorimetric diagnostic systems . Among various NPs, AuNPs have gained increasing attention in the development of biosensors owning to their fascinating optical properties which are related to the strong surface plasmon resonance (SPR) absorption. SPR is generated by the incidence of light on a metal surface, causing collective coherent oscillation of conduction electrons. If frequency of the light source matches with that of the surface plasmon, amplitude of the electron oscillation increases which is known as SPR or localized SPR (LSPR) in NPs, resulting in strong absorption of the incident light which can be measured using a UV-Vis spectrometer . The SPR can be affected by shape, size, and the dielectric constant of metal and the distance among the NPs . Dispersed AuNPs, as one of the plasmonic NPs, have shown a specific color or LSPR band which may change into another color or LSPR band upon the addition of external materials such as biomolecules or ions [163, 164]. Recently, Kim and coworkers designed a colorimetric test based on AuNPs and thiol-modified probes for targeting partial genomic regions of MERS-CoV . As shown in Figure 3, they designed thiol-modified probes linked to citrate-coated AuNPs via strong Au–S interactions to target the upstream of the E protein gene (upE) and open reading frames (ORF) 1a on MERS-CoV. A combination of thiol-modified probes and AuNPs at the presence of MgCl2 led to the aggregation of AuNPs with a reduction in intensity and an increase in bandwidth of LSPR band as well as the emergence of new bands at a longer wavelength. However, the presence of target DNA led to the formation of long assemblies of dsDNA on the surface of AuNPs and shielded the disulfide bands leading to inhibition of the AuNP aggregation by MgCl2 which limited the color change for diagnosis of MERS-CoV.
AuNP can be also used in combination with other diagnostic systems such as fiber-optic biosensors to achieve sensitive virus detection. For example, Huang et al. developed a localized surface plasmon-coupled fluorescence (LSPCF) fiber-optic biosensor utilizing AuNPs for the identification of SARS-CoV N protein. Compared to the enzyme-linked immunosorbent assay (ELISA) toward the same monoclonal antibodies, the LSPCF fiber-optic biosensor exhibited a 104 time limit detection improvement .
4.7. Nanotechnology in Electrochemical Sensing of Coronavirus Infections
Another analytical methodology that has explored for detection of viral infections is the electrochemical sensing [167, 168]. Conventional electrochemical sensors include an electrolyte, a diffusion barrier, a sensing electrode (as transduction element), and a counter-reference electrode, resulting electrical signal from the interaction of target analyte and recognition layer of sensing electrode. Fascinating properties of NPs (especially metallic and semiconductor NPs) including high surface area, conductivity, and catalytic properties have led to their use in (i) surface immobilization of biomolecules, (ii) enrichment of electron transfer, (iii) effective catalysis, and (iv) labeling biomolecules . The electrochemical immunosensors are comprised of an electrode surface immobilization with recognition component (i.e., antibody or antigen) and gained promising attention as reliable and efficient sensing platform for detection of viral infections [170, 171]. Layqah and Eissa developed a competitive electrochemical immunosensor for sensitive, cost-effective, and user-friendly sensing for the multiplexed detection of different CoVs, as depicted in Figure 4. AuNPs were electrodeposited on a carbon electrode (DEP) (AuNP/DEP) to increase the electron transfer efficiency and provide a higher surface area to improve the biosensor response signal due to presence of more immobilized biomolecules . AuNP/DEP was modified with different antigens such as MERS-CoV, HCoV (Oc43 N), and bovine serum albumin (BSA) as a control electrode. The addition of constant concentration of antibody to the sample containing free virus and immobilized MERS-CoV protein, HCoV, and BSA changed the voltammetric response which can be measured via square wave voltammetry (SWV). Results indicated a linear correlation between the sensor responses and the concentrations as well as lower detection limits for artificial spiked nasal samples of MERS-CoV and HCoV.
In addition to AuNPs, QDs have been employed for the development of biosensors. Recently, Roh developed a biochip through modification by SARS-CoV N protein and QD-conjugated RNA oligonucleotide and tested the inhibitor screening of SARS-CoV N protein ability of fabricated biochip using several polyphenolic compounds (Figure 5). Among different polyphenolic compounds, gallate and (-)-gallocatechin gallate with anti-HIV properties showed higher and equal half-maximal inhibitory concentration (IC50) values on a QDs-RNA oligonucleotide biochip in comparison with other polyphenolic compounds. The results revealed that biochips not only led to the specific detection of the SARS-CoV N protein but also could be used for inhibitor screening of SARS-CoV N protein . Moreover, Zhu and coworkers coupled NP-based biosensors (NBS) with reverse transcription loop-mediated isothermal amplification (RT-LAMP) for the diagnosis of COVID-19 which resulted in the selective and sensitive detection of SARS-CoV-2 . Taken together, electrochemical sensing might be promising technique for the rapid detection of CoV infections. For more detailed information, interested reader is referred to excellent review on this topic by Kaushik and coworkers .
4.8. Nanotechnology in RT-PCR-Based Detection of Coronavirus Infections
As mentioned earlier, RT-PCR is the main conventical diagnostic method for CoV infections. This method requires the extraction of high-purity nucleic acids to produce strong signals and low false negative results [174, 175]. Regarding that present methods for the extraction of nucleic acids using filtration or centrifugation are very time-consuming and labor-intensive, the application magnetic NPs in sample preparation have fascinated more attention. Magnetic NPs can be easily separated from the media using an external magnetic field during the sample preparation, also called preenrichment . In recent years, magnetic NPs have gained promising attention as solid-phase adsorbents of various biomacromolecules; this method is superior over conventional procedures due to shorter processing times, decreased chemical consumption, and simpler procedure via automation . For this purpose, Zhao and coworkers developed poly(amino ester) with carboxyl group- (PC-) coated magnetic NPs (pcMNPs) for the extraction of SARS-CoV-2 RNA, resulting in the sensitive detection of COVID-19 via RT-PCR . In comparison to column-based nucleic acid extraction methods, pcMNPs showed a rapid simple extraction with high purity and productivity with the assistance of an external magnet, resulting in time-consuming RNA extraction for the diagnosis of COVID-19. Taken together, as presented in Table 3, NPs might be promising materials for the detection and extraction of CoV infections. Further experiments are still necessary to assess their safety and efficacy.
4.9. Nanotechnology in the Treatment of Coronavirus Infections
The absence of specific anti-CoV drugs and also the continuous advent of new CoV infections rise the demand for specific antiviral therapies. As mentioned before, current COVID-19 therapies are deduced from MERS-CoV, SARS-CoV, and H1N1 influenza which are a combination of different antiviral agents including protease inhibitors, nucleoside analogs, and corticosteroids. Nowadays, with the advancement of nanotechnology, a growing focus has been devoted to nanoscale antiviral materials as efficient modulating process platforms for viral infections . Nanoscale antiviral materials can be used for (i) targeted delivery of pharmacological agents to the sites of CoV infections, (ii) prolonged drug release for efficient treatment, (iii) decreasing the drug toxicity and associated side effects, (iv) improving the drug efficacy and potency, (v) delivery of gene and/or immune-based therapies, and (vi) targeting the virus entrance mechanism. Numerous nanoscale antiviral materials have been designed to interfere with the virus and cell receptor interactions. In fact, the high surface-to-volume ratio of NPs led to their efficient attachment to the healthy or noncontaminated cells which result in blocking virus entrance into cells .
Recently, the ability of carbon quantum dots (CQDs) to interfere with the HIV-1 and herpes simplex virus type 1 cell entrance has led to the use of boronic acid-functionalized CQDs for the treatment of HCoV-229E infection [181–183]. Łoczechin et al. synthesized seven CQD derivatives which had dose-dependent anti-HCoV-229E activity . Among the CQDs, just boronic acid-functionalized CQDs exhibited anti-HCoV-229E activity; but the low content boronic acid derivatives of CQDs showed lower EC50 in comparison to the higher content of boronic acid derivatives. Results also revealed that the boronic acid derivatives of CQDs not only caused an interaction with cell entry factors but also affect the genomic replication of the HCoV-229E virus. Consequently, boronic acid-functionalized CQDs might be regarded as a therapeutic agent for COVID-19. Moreover, in the functionalization of nanomaterials to improve their antiviral activities, their shape plays an effective role in their antiviral activity. However, most of the reported antiviral nanomaterials are spherical; nonspherical nanomaterials may display higher antiviral effects compared to their spherical peers . Recently, Zhou et al. reported that mercaptoethane sulfonate-functionalized bovine serum albumin- (BSA-) coated tellurium star-shaped NPs (Te/BSA NPs) are able to suppress the internalization process of porcine epidemic diarrhea virus (PEDV), a model of CoV, more than the spherical Te/BSA NPs, which might be due to its more interactions with viruses. Moreover, free mercaptoethane sulfonate did not show any significant antiviral effect on PRRSV probably because of its free rotation which may lead to its weak binding affinity to viral proteins. The star-shaped Te/BSA NPs showed higher distribution in the cytoplasm leading to a decline in reactive oxygen species (ROS) content of porcine reproductive and respiratory syndrome virus- (PRRSV-) infected MARC-145 cells, hence resulting in cell apoptosis or even necrosis . Apart from interfering with protein S-receptor interaction, NPs have been applied to target vacuolar ATPase (V-ATPase) activity, which pumps protons into endosomal compartments. Recently, Hu and coworkers prepared poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PEG-PLGA) NPs to target feline CoV (FCoV) infection . They encapsulated diphyllin, a natural V-ATPase inhibitor into PEG-PLGA NPs to reduce its off-target effect and increase its antiviral activity. PEG-PLGA NPs showed dose-dependent endosomal acidification inhibition activity in (felis catus whole fetus-4) cell line as well as in vitro prominent antiviral effect against the feline infectious peritonitis virus (FIPV), a biotype of FCoV.
Recently, the combination of nanotechnology and human natural stem cell-based therapies has led to emergence of new strategies in treatment of various deceases. For example, “LIFNano” (leukemia inhibitory factor nanoformulation), a synthetic stem cell product with the current indication in multiple sclerosis (MS) and rheumatoid arthritis, has attracted much interest in the management of COVID-19 pneumonia [188, 189]. The surface ligands of COVID-19 have also attracted the attention of NanoViricides company to develop a nanoformulation based on nanoviricide® technology . Nanoviricide®, an antiviral polymeric nanomicelle-based formulation for influenza, HIV, herpes, etc., comprises a single-chain polymer conjugated to specific ligands that help in engulfing or coating the virus, resulting in virus neutralization and destabilization and may be viral genome attacking . Taken together, nanotechnology-based antiviral materials might be promising options for the treatment of CoV infections. Further experiments are, however, necessary to assess their safety and efficacy.
Combating CoV infections is an enormous challenge for healthcare systems, primarily due to its high transmittance rate, and the virus potential to survive through multiple mutations. Up to now, few drugs have been approved for CoV infections (especially COVID-19); however, the development and design of old and new drugs are still urgently necessary for humans. Currently, there are some authorized vaccines for COVID-19 protection, but it is highly important to prevent its spread by various techniques, such as the isolation of infected patients, the use of personal protective devices and disinfectants, and rapid and early detection systems. As new systems, the benefits of nanotechnology result in the design and development of different nanoscale systems for the prevention, treatment, and diagnosis of CoV infections. Nanotechnology-based formulations can offer controlled and sustained release of antigens and therapeutic agents, as well as interfering with the entry of the virus into cells to enhance the prevention and treatment measures toward CoV infections. Moreover, nanotechnology can help in the development of rapid, cost-effective, and high-sensitive diagnostics systems for CoV infections. However, the majority of studies in the field of CoV nanotechnology continues in the preliminary drug development phases, and problems remain until these systems can progress into clinical use. The efficacy, stability, and safety of nanoscale-based prevention and therapeutic and diagnosis systems must be evaluated by relevant clinical endpoints. Ongoing studies to address these issues must continue. Ultimately, nanotechnology provides several interesting systems to promote the fields of CoV prevention, treatment, and diagnosis.
Conflicts of Interest
The authors declare that they have no conflict of interest.
This work was financially supported by the Shiraz University of Medical Sciences.
- H. Lu, “Drug treatment options for the 2019-new coronavirus (2019-nCoV),” Bioscience Trends, vol. 14, no. 1, pp. 69–71, 2020.
- M. L. Holshue, C. DeBolt, S. Lindquist et al., “First case of 2019 novel coronavirus in the United States,” New England Journal of Medicine, vol. 382, no. 10, pp. 929–936, 2020.
- J. Gao, Z. Tian, and X. Yang, “Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies,” Bioscience Trends, vol. 14, no. 1, pp. 72-73, 2020.
- W.-H. Chen, U. Strych, P. J. Hotez, and M. E. Bottazzi, “The SARS-CoV-2 vaccine pipeline: an overview,” Current Tropical Medicine Reports, vol. 7, no. 2, pp. 61–64, 2020.
- P. S. Kim and S. W. Read, “Nanotechnology and HIV: potential applications for treatment and prevention,” Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, vol. 2, no. 6, pp. 693–702, 2010.
- X. Zhu, X. Wang, L. Han et al., “Reverse transcription loop-mediated isothermal amplification combined with nanoparticles-based biosensor for diagnosis of COVID-19,” medRxiv, 2020.
- L. Chen and J. Liang, “An overview of functional nanoparticles as novel emerging antiviral therapeutic agents,” Materials Science and Engineering: C, vol. 112, p. 110924, 2020.
- R. Rupp, S. L. Rosenthal, and L. R. Stanberry, “VivaGel (SPL7013 Gel): a candidate dendrimer--microbicide for the prevention of HIV and HSV infection,” International Journal of Nanomedicine, vol. 2, no. 4, pp. 561–566, 2007.
- M.-K. Tsang, W. Ye, G. Wang, J. Li, M. Yang, and J. Hao, “Ultrasensitive detection of Ebola virus oligonucleotide based on upconversion nanoprobe/nanoporous membrane system,” ACS Nano, vol. 10, no. 1, pp. 598–605, 2015.
- Z. Liu, C. Shang, H. Ma, and M. You, “An upconversion nanoparticle-based photostable FRET system for long-chain DNA sequence detection,” Nanotechnology, vol. 31, no. 23, 2020.
- K. M. Tyo, A. B. Lasnik, L. Zhang et al., “Sustained-release Griffithsin nanoparticle-fiber composites against HIV-1 and HSV-2 infections,” Journal of Controlled Release, vol. 321, pp. 84–99, 2020.
- S. Dhakal, S. Renu, S. Ghimire et al., “Mucosal immunity and protective efficacy of intranasal inactivated influenza vaccine is improved by chitosan nanoparticle delivery in pigs,” Frontiers in Immunology, vol. 9, p. 934, 2018.
- M. Cascella, M. Rajnik, A. Cuomo, S. C. Dulebohn, and R. Di Napoli, “Features, evaluation and treatment coronavirus (COVID-19),” in Statpearls, StatPearls Publishing, 2020.
- J. F.-W. Chan, K. K.-W. To, H. Tse, D.-Y. Jin, and K.-Y. Yuen, “Interspecies transmission and emergence of novel viruses: lessons from bats and birds,” Trends in Microbiology, vol. 21, no. 10, pp. 544–555, 2013.
- L.-s. Wang, Y.-r. Wang, D.-w. Ye, and Q.-q. Liu, “Erratum to ``A review of the 2019 Novel Coronavirus (COVID-19) based on current evidence'' [International Journal of Antimicrobial Agents 55/6 (2020) 105948],” International Journal of Antimicrobial Agents, vol. 56, no. 3, p. 106137, 2020.
- K. Shen, Y. Yang, T. Wang et al., “Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts’ consensus statement,” World Journal of Pediatrics, vol. 16, pp. 223–231, 2020.
- W.-j. Guan, Z.-y. Ni, Y. Hu et al., “Clinical characteristics of 2019 novel coronavirus infection in China,” MedRxiv, 2020.
- L. Wang, W. He, X. Yu et al., “Coronavirus disease 2019 in elderly patients: characteristics and prognostic factors based on 4-week follow-up,” Journal of Infection, vol. 80, no. 6, pp. 639–645, 2020.
- L. J. Saif, “Vaccines for COVID-19: perspectives, prospects, and challenges based on candidate SARS, MERS, and animal coronavirus vaccines,” European Medical Journal, 2020.
- S. Rauch, E. Jasny, K. E. Schmidt, and B. Petsch, “New vaccine technologies to combat outbreak situations,” Frontiers in Immunology, vol. 9, p. 1963, 2018.
- R. L. Roper and K. E. Rehm, “SARS vaccines: where are we?” Expert Review of Vaccines, vol. 8, no. 7, pp. 887–898, 2014.
- L. Enjuanes, M. L. DeDiego, E. Álvarez, D. Deming, T. Sheahan, and R. Baric, “Vaccines to prevent severe acute respiratory syndrome coronavirus-induced disease,” Virus Research, vol. 133, no. 1, pp. 45–62, 2008.
- N. I. Nii-Trebi, “Emerging and neglected infectious diseases: insights, advances, and challenges,” BioMed Research International, vol. 2017, Article ID 5245021, 15 pages, 2017.
- M. Z. Zhai, C. T. Lye, and A. S. Kesselheim, “Need for transparency and reliable evidence in emergency use authorizations for coronavirus disease 2019 (COVID-19) therapies,” JAMA Internal Medicine, vol. 180, no. 9, pp. 1145-1146, 2020.
- World Health Organization, Home Care for Patients with Suspected Novel Coronavirus (nCoV) Infection Presenting with Mild Symptoms and Management of Contacts: Interim Guidance, 20 January 2020, 2020.
- K. C. Halfpenny and D. W. Wright, “Nanoparticle detection of respiratory infection,” Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, vol. 2, no. 3, pp. 277–290, 2010.
- C. Reusken, H. Mou, G. J. Godeke et al., “Specific serology for emerging human coronaviruses by protein microarray,” Eurosurveillance, vol. 18, no. 14, p. 20441, 2013.
- U. Buchholz, M. A. Müller, A. Nitsche et al., “Contact investigation of a case of human novel coronavirus infection treated in a German hospital, October-November 2012,” Eurosurveillance, vol. 18, no. 8, p. 20406, 2013.
- K. Shirato, S. Semba, S. A. El-Kafrawy et al., “Development of fluorescent reverse transcription loop-mediated isothermal amplification (RT-LAMP) using quenching probes for the detection of the Middle East respiratory syndrome coronavirus,” Journal of Virological Methods, vol. 258, pp. 41–48, 2018.
- M. Espy, J. Uhl, L. Sloan et al., “Real-time PCR in clinical microbiology: applications for routine laboratory testing,” Clinical Microbiology Reviews, vol. 19, no. 1, pp. 165–256, 2006.
- V. Corman, T. Bleicker, S. Brünink, and M. Zambon, Diagnostic detection of Wuhan coronavirus 2019 by real-time RT-PCR, vol. 13, World Health Organization, Geneva, 2020.
- A. Zumla, J. F. Chan, E. I. Azhar, D. S. Hui, and K.-Y. Yuen, “Coronaviruses—drug discovery and therapeutic options,” Nature Reviews Drug Discovery, vol. 15, no. 5, p. 327, 2016.
- T. P. Sheahan, A. C. Sims, S. R. Leist et al., “Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV,” Nature Communications, vol. 11, no. 1, pp. 1–14, 2020.
- M. Khalid, F. Al Rabiah, B. Khan, A. Al Mobeireek, T. S. Butt, and E. Al Mutairy, “Ribavirin and interferon-α2b as primary and preventive treatment for Middle East respiratory syndrome coronavirus: a preliminary report of two cases,” Antiviral Therapy, vol. 20, no. 1, pp. 87–91, 2015.
- U. Ströher, A. DiCaro, Y. Li et al., “Severe acute respiratory syndrome-related coronavirus is inhibited by interferon-α,” Journal of Infectious Diseases, vol. 189, no. 7, pp. 1164–1167, 2004.
- D. Falzarano, E. de Wit, C. Martellaro, J. Callison, V. J. Munster, and H. Feldmann, “Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin,” Scientific Reports, vol. 3, no. 1, p. 1686, 2013.
- B. Jones, E. Ma, J. Peiris et al., “Prolonged disturbances of in vitro cytokine production in patients with severe acute respiratory syndrome (SARS) treated with ribavirin and steroids,” Clinical & Experimental Immunology, vol. 135, no. 3, pp. 467–473, 2004.
- T. G. Ksiazek, D. Erdman, C. S. Goldsmith et al., “A novel coronavirus associated with severe acute respiratory syndrome,” New England Journal of Medicine, vol. 348, no. 20, pp. 1953–1966, 2003.
- M. Costanzo, M. De Giglio, and G. Roviello, “SARS-CoV-2: recent reports on antiviral therapies based on lopinavir/ritonavir, darunavir/umifenovir, hydroxychloroquine, remdesivir, favipiravir and other drugs for the treatment of the new coronavirus,” Current Medicinal Chemistry, vol. 27, no. 27, pp. 4536–4541, 2020.
- M. Wang, R. Cao, L. Zhang et al., “Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro,” Cell Research, vol. 30, no. 3, pp. 269–271, 2020.
- H. Li, S.-M. Liu, X.-H. Yu, S.-L. Tang, and C.-K. Tang, “Coronavirus disease 2019 (COVID-19): current status and future perspective,” International Journal of Antimicrobial Agents, vol. 55, article 105951, 2020.
- F. Touret and X. de Lamballerie, “Of chloroquine and COVID-19,” Antiviral Research, vol. 177, article 104762, 2020.
- J. Liu, R. Cao, M. Xu et al., “Bi-directional differentiation of single bronchioalveolar stem cells during lung repair,” Cell Discovery, vol. 6, no. 1, pp. 1–4, 2020.
- H. Liang and G. Acharya, “Novel corona virus disease (COVID-19) in pregnancy: what clinical recommendations to follow?” Acta Obstetricia et Gynecologica Scandinavica, vol. 99, no. 4, pp. 439–442, 2020.
- C. D. Russell, J. E. Millar, and J. K. Baillie, “Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury,” The Lancet, vol. 395, no. 10223, pp. 473–475, 2020.
- S. Pei, X. Yuan, Z. Z. Zhang et al., “Convalescent plasma to treat COVID-19: Chinese strategy and experiences,” medRxiv, 2020.
- J.-H. Yoo, “Convalescent plasma therapy for corona virus disease 2019: a long way to go but worth trying,” Journal of Korean Medical Science, vol. 35, no. 14, 2020.
- National Research Project for SARS, Beijing Group, “The involvement of natural killer cells in the pathogenesis of severe acute respiratory syndrome,” American Journal of Clinical Pathology, vol. 121, no. 4, pp. 507–511, 2004.
- Q. Hammer, T. Rückert, and C. Romagnani, “Natural killer cell specificity for viral infections,” Nature Immunology, vol. 19, no. 8, pp. 800–808, 2018.
- E. El Agha, R. Kramann, R. K. Schneider et al., “Mesenchymal stem cells in fibrotic disease,” Cell Stem Cell, vol. 21, no. 2, pp. 166–177, 2017.
- L. A. Ortiz, M. DuTreil, C. Fattman et al., “Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury,” Proceedings of the National Academy of Sciences, vol. 104, no. 26, pp. 11002–11007, 2007.
- Y. Yang, M. S. Islam, J. Wang, Y. Li, and X. Chen, “Traditional Chinese medicine in the treatment of patients infected with 2019-new coronavirus (SARS-CoV-2): a review and perspective,” International Journal of Biological Sciences, vol. 16, no. 10, p. 1708, 2020.
- National Institute of Allergy and Infectious Diseases (NIAID), “Safety and immunogenicity study of 2019-nCoV vaccine (mRNA-1273) for prophylaxis of SARS-CoV-2 infection (COVID-19),” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04283461.
- A. Pollard, “A study of a candidate COVID-19 vaccine (COV001),” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04324606.
- M. P. Mammen, “Safety, tolerability and immunogenicity of INO-4800 followed by electroporation in healthy volunteers for COVID19,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04447781.
- I. Hassan, “Application of BCG vaccine for immune-prophylaxis among Egyptian healthcare workers during the pandemic of COVID-19,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04350931.
- N. Curtis, “BCG vaccination to protect healthcare workers against COVID-19,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04327206.
- J. D. Cirillo, “BCG vaccine for health care workers as defense against COVID 19,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04348370.
- M. Bosaeed, “A clinical trial to determine the safety and immunogenicity of healthy candidate MERS-CoV vaccine (MERS002),” 2019, February 2021, https://ClinicalTrials.gov/show/NCT04170829.
- A. V. Hill, “Safety and immunogenicity of a candidate MERS-CoV vaccine (MERS001),” 2018, February 2021, https://ClinicalTrials.gov/show/NCT03399578.
- L.-J. Chang, “Safety and immunity of Covid-19 aAPC vaccine,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04299724.
- L.-J. Chang, “Immunity and safety of Covid-19 synthetic minigene vaccine,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04276896.
- F. Zhu, “A phase II clinical trial to evaluate the recombinant vaccine for COVID-19 (Adenovirus Vector),” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04341389.
- R. O. Dillman, “Phase I-II trial of dendritic cell vaccine to prevent COVID-19 in adults,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04386252.
- I. Dolzhikova, “Study of safety and immunogenicity of BVRS-GamVac,” 2019, February 2021, https://ClinicalTrials.gov/show/NCT04130594.
- M. M. Addo, “Safety and immunogenicity of the candidate vaccine MVA-MERS-S_DF-1 against MERS,” 2019, February 2021, https://ClinicalTrials.gov/show/NCT04119440.
- T. Zubkova, “Study of safety and immunogenicity of BVRS-GamVac-Combi,” 2019, February 2021, https://ClinicalTrials.gov/show/NCT04128059.
- J. C. Cataño, “Performance evaluation of BCG vaccination in healthcare personnel to reduce the severity of COVID-19 infection,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04362124.
- BioNTech Responsible Person, “A trial investigating the safety and effects of four BNT162 vaccines against COVID-2019 in healthy and immunocompromised adults,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04380701.
- Pfizer CT.gov Call Center, “Study to describe the safety, tolerability, immunogenicity, and efficacy of RNA vaccine candidates against COVID-19 in healthy individuals,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04368728.
- A. Bourinbayar, “Tableted COVID-19 therapeutic vaccine,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04380532.
- National Institute of Allergy and Infectious Diseases (NIAID), “Phase I study of a vaccine for severe acute respiratory syndrome (SARS),” 2004, February 2021, https://ClinicalTrials.gov/show/NCT00099463.
- S. Y. Li, “Bone marrow-derived mesenchymal stem cell treatment for severe patients with coronavirus disease 2019 (COVID-19),” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04346368.
- G. Carcano, “Monocytes and NK cells activity in Covid-19 patients,” 2020, NCT04375176, https://ClinicalTrials.gov/show/NCT04375176.
- S. Viatte, “Immune cells in inflammatory arthritis with coronaviruses, including COVID-19,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04363047.
- A. Hernandez-Ruiz, “Safety and efficacy of intravenous Wharton’s jelly derived mesenchymal stem cells in acute respiratory distress syndrome due to COVID 19,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04390152.
- A. Camacho-Ortiz, “Convalescent plasma compared to the best available therapy for the treatment of SARS-CoV-2 pneumonia,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04358783.
- H. Lu, “Anti-SARS-CoV-2 inactivated convalescent plasma in the treatment of COVID-19,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04292340.
- National Institute of Allergy and Infectious Diseases (NIAID), “Collection of anti-SARS-CoV-2 immune plasma,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04344977.
- A. F. Zuluaga, “Inactivated convalescent plasma as a therapeutic alternative in patients CoViD-19,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04385186.
- J. M. A. Cabrera, “Convalescent plasma for patients with COVID-19: a pilot study,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04332380.
- J. M. A. Cabrera, “Convalescent plasma for patients with COVID-19: a randomized, single blinded, parallel, controlled clinical study,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04332835.
- R. T. Davey, “Safety, tolerability, and pharmacokinetics of SAB-301 in healthy adults,” 2016, February 2021, https://ClinicalTrials.gov/show/NCT02788188.
- D. Tan, “COVID-19 ring-based prevention trial with lopinavir/ritonavir,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04321174.
- O. Kentab, “Evaluating the efficacy of artesunate in adults with mild symptoms of COVID-19,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04387240.
- J. Kirmani, “Hydroxychloroquine as chemoprevention for COVID-19 for high risk healthcare workers,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04345653.
- H. Elalfy, “New antiviral drugs for treatment of COVID-19,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04392427.
- Gilead Sciences, “Study to evaluate the safety and antiviral activity of Remdesivir (GS-5734™) in participants with moderate coronavirus disease (COVID-19) compared to standard of care treatment,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04292730.
- National Institute of Allergy and Infectious Diseases (NIAID), “Adaptive COVID-19 treatment trial (ACTT),” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04280705.
- Z. Yang, “A real world study for the efficacy and safety of large dose tanreqing injection in the treatment of patients with novel coronavirus pneumonia (COVID-19),” 2020, February 2021, http://www.chictr.org.cn/showprojen.aspx?proj=48881.
- S. Wen, “Clinical study for Gu-Biao Jie-Du-Ling in preventing of novel coronavirus pneumonia (COVID-19) in children,” 2020, February 2021, http://www.chictr.org.cn/showprojen.aspx?proj=48965.
- H. Lu, “Clinical trial for tanreqing capsules in the treatment of novel coronavirus pneumonia (COVID-19),” 2020, February 2021, http://www.chictr.org.cn/showprojen.aspx?proj=49425.
- M. Penglin, “Shen-Fu injection in the treatment of severe novel coronavirus pneumonia (COVID-19): a multicenter, randomized, open-label, controlled trial,” 2020, February 2021, http://www.chictr.org.cn/showprojen.aspx?proj=49866.
- X. Zheng, “A multicenter, randomized, open, controlled trial for the efficacy and safety of Shen-Qi Fu-Zheng injection in the treatment of novel coronavirus pneumonia (COVID-19),” 2020, February 2021, http://www.chictr.org.cn/showprojen.aspx?proj=49220.
- Z. Nanshan, “A randomized, open-label, blank-controlled trial for Lian-Hua Qing-Wen Capsule /Granule in the treatment of novel coronavirus pneumonia (COVID-19),” 2020, February 2021, http://www.chictr.org.cn/showprojen.aspx?proj=48889.
- W. Daowen, “A randomized, open-label, blank-controlled, multicenter trial for Shuang-Huang-Lian oral solution in the treatment of novel coronavirus pneumonia (COVID-19),” 2020.
- Y. Yi, “A randomized controlled trial for honeysuckle decoction in the treatment of patients with novel coronavirus (COVID-19) infection,” 2020, February 2021, http://www.chictr.org.cn/showprojen.aspx?proj=49502.
- X. Zheng, “A multicenter, randomized, open and controlled trial for the efficacy and safety of Kang-Bing-Du granules in the treatment of novel coronavirus pneumonia (COVID-19),” 2020, February 2021, http://www.chictr.org.cn/showprojen.aspx?proj=49138.
- L. Hua, “Efficacy and safety of Jing-Yin granule in the treatment of novel coronavirus pneumonia (COVID-19) wind-heat syndrome,” 2020, February 2021, http://www.chictr.org.cn/showprojen.aspx?proj=50089.
- W. Zhang, “A randomized, open-label, controlled trial for the safety and efficiency of Kesuting syrup and Keqing capsule in the treatment of mild and moderate novel coronavirus pneumonia (COVID-19),” 2020, February 2021, http://www.chictr.org.cn/showprojen.aspx?proj=49666.
- H. Lu, “A multicenter, randomized, open, parallel controlled trial for the evaluation of the effectiveness and safety of Xiyanping injection in the treatment of common type novel coronavirus pneumonia (COVID-19),” 2020, February 2021, http://www.chictr.org.cn/showprojen.aspx?proj=49762.
- X. Wei, “Efficacy and safety of Xue-Bi-Jing injection in the treatment of severe cases of novel coronavirus pneumonia (COVID-19),” 2020, February 2021, http://www.chictr.org.cn/showprojen.aspx?proj=50306.
- D. H. Alamdari, “Clinical application of methylene blue for treatment of Covid-19 patients,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04370288.
- L. Berra, “NO prevention of COVID-19 for healthcare providers,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04312243.
- F. Annoni, “Angiotensin-(1,7) treatment in COVID-19: the ATCO trial,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04332666.
- R. W. Alexander, “Use of cSVF via IV deployment for residual lung damage after symptomatic COVID-19 infection,” 2020, February 2021, https://ClinicalTrials.gov/show/NCT04326036.
- S. Lin, R. Shen, J. He, X. Li, and X. Guo, “Molecular modeling evaluation of the binding effect of ritonavir, lopinavir and darunavir to severe acute respiratory syndrome coronavirus 2 proteases,” bioRxiv, 2020.
- F. Pulido, J. R. Arribas, R. Delgado et al., “Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and two nucleosides for maintenance therapy of HIV,” AIDS, vol. 22, no. 2, pp. F1–F9, 2008.
- E. De Clercq, “New nucleoside analogues for the treatment of hemorrhagic fever virus infections,” Chemistry, an Asian Journal, vol. 14, no. 22, pp. 3962–3968, 2019.
- E. S. Amirian and J. K. Levy, “Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses,” One Health, vol. 9, p. 100128, 2020.
- N. Chen, M. Zhou, X. Dong et al., “Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study,” The Lancet, vol. 395, no. 10223, pp. 507–513, 2020.
- C. A. Devaux, J.-M. Rolain, P. Colson, and D. Raoult, “New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?” International Journal of Antimicrobial Agents, vol. 55, article 105938, 2020.
- C. Wu, X. Chen, Y. Cai et al., “Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China,” JAMA Internal Medicine, vol. 180, no. 7, pp. 934–943, 2020.
- C. Sohrabi, Z. Alsafi, N. O’Neill et al., “World Health Organization declares global emergency: a review of the 2019 novel coronavirus (COVID-19),” International Journal of Surgery, vol. 76, 2020.
- Y. Cheng, R. Wong, Y. Soo et al., “Use of convalescent plasma therapy in SARS patients in Hong Kong,” European Journal of Clinical Microbiology and Infectious Diseases, vol. 24, no. 1, pp. 44–46, 2005.
- M. Abedi, S. S. Abolmaali, M. Abedanzadeh, F. Farjadian, S. Mohammadi Samani, and A. M. Tamaddon, “Core-shell imidazoline-functionalized mesoporous silica superparamagnetic hybrid nanoparticles as a potential theranostic agent for controlled delivery of platinum(II) compound,” International Journal of Nanomedicine, vol. Volume 15, pp. 2617–2631, 2020.
- M. Abedi, S. S. Abolmaali, M. Abedanzadeh, S. Borandeh, S. M. Samani, and A. M. Tamaddon, “Citric acid functionalized silane coupling versus post-grafting strategy for dual pH and saline responsive delivery of cisplatin by Fe3O4/carboxyl functionalized mesoporous SiO2 hybrid nanoparticles: a-synthesis, physicochemical and biological characterization,” Materials Science and Engineering: C, vol. 104, p. 109922, 2019.
- Z. Rahiminezhad, A. M. Tamaddon, S. Borandeh, and S. S. Abolmaali, “Janus nanoparticles: new generation of multifunctional nanocarriers in drug delivery, bioimaging and theranostics,” Applied Materials Today, vol. 18, p. 100513, 2020.
- V. Alimardani, S. S. Abolmaali, A. M. Tamaddon, and M. Ashfaq, “Recent advances on microneedle arrays-mediated technology in cancer diagnosis and therapy,” Drug Delivery and Translational Research, 2020.
- V. Alimardani, S. S. Abolmaali, G. Yousefi et al., “Microneedle arrays combined with nanomedicine approaches for transdermal delivery of therapeutics,” Journal of Clinical Medicine, vol. 10, no. 2, p. 181, 2021.
- T. S. Hauck, S. Giri, Y. Gao, and W. C. W. Chan, “Nanotechnology diagnostics for infectious diseases prevalent in developing countries,” Advanced Drug Delivery Reviews, vol. 62, no. 4-5, pp. 438–448, 2010.
- L. Singh, H. G. Kruger, G. E. Maguire, T. Govender, and R. Parboosing, “The role of nanotechnology in the treatment of viral infections,” Therapeutic Advances in Infectious Disease, vol. 4, no. 4, pp. 105–131, 2017.
- A. Bolhassani, S. Javanzad, T. Saleh, M. Hashemi, M. R. Aghasadeghi, and S. M. Sadat, “Polymeric nanoparticles: potent vectors for vaccine delivery targeting cancer and infectious diseases,” Human Vaccines & Immunotherapeutics, vol. 10, no. 2, pp. 321–332, 2014.
- S. Taghizadeh, V. Alimardani, P. L. Roudbali, Y. Ghasemi, and E. Kaviani, “Gold nanoparticles application in liver cancer,” Photodiagnosis and Photodynamic Therapy, vol. 25, pp. 389–400, 2019.
- A. Aiacoboae, T. Gheorghe, I. I. Lungu et al., “Chapter 2 - applications of nanoscale drugs carriers in the treatment of chronic diseases,” in Nanostructures for Novel Therapy, D. Ficai and A. M. Grumezescu, Eds., pp. 37–55, Elsevier, 2017.
- G. Acharya, A. K. Mitra, and K. Cholkar, “Chapter 10 - nanosystems for diagnostic imaging, biodetectors, and biosensors,” in Emerging Nanotechnologies for Diagnostics, Drug Delivery and Medical Devices, A. K. Mitra, K. Cholkar, and A. Mandal, Eds., pp. 217–248, Elsevier, Boston, 2017.
- J. Bhagwan, N. Kumar, and Y. Sharma, “Chapter 13 - fabrication, characterization, and optimization of mnxoy nanofibers for improved supercapacitive properties,” in Nanomaterials Synthesis, Y. B. Pottathara, S. Thomas, N. Kalarikkal, Y. Grohens, and V. Kokol, Eds., pp. 451–481, Elsevier, 2019.
- P. P. Coll, V. W. Costello, G. A. Kuchel, J. Bartley, and J. E. McElhaney, “The prevention of infections in older adults: vaccination,” Journal of the American Geriatrics Society, vol. 68, no. 1, pp. 207–214, 2019.
- M. S. Diamond and T. C. Pierson, “The challenges of vaccine development against a new virus during a pandemic,” Cell Host & Microbe, vol. 27, no. 5, pp. 699–703, 2020.
- N. M. Okba, V. S. Raj, and B. L. Haagmans, “Middle East respiratory syndrome coronavirus vaccines: current status and novel approaches,” Current Opinion in Virology, vol. 23, pp. 49–58, 2017.
- M.-G. Kim, J. Y. Park, Y. Shon, G. Kim, G. Shim, and Y.-K. Oh, “Nanotechnology and vaccine development,” Asian Journal of Pharmaceutical Sciences, vol. 9, no. 5, pp. 227–235, 2014.
- S. Al-Halifa, L. Gauthier, D. Arpin, S. Bourgault, and D. Archambault, “Nanoparticle-based vaccines against respiratory viruses,” Frontiers in Immunology, vol. 10, p. 22, 2019.
- E. P. Rybicki, “Plant molecular farming of virus-like nanoparticles as vaccines and reagents,” Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, vol. 12, no. 2, article e1587, 2020.
- A. Parodi, R. Molinaro, M. Sushnitha et al., “Bio-inspired engineering of cell- and virus-like nanoparticles for drug delivery,” Biomaterials, vol. 147, pp. 155–168, 2017.
- H.-W. Chen, C.-Y. Huang, S.-Y. Lin et al., “Synthetic virus-like particles prepared via protein corona formation enable effective vaccination in an avian model of coronavirus infection,” Biomaterials, vol. 106, pp. 111–118, 2016.
- L. C.-W. Lin, C.-Y. Huang, B.-Y. Yao et al., “Viromimetic STING agonist-loaded hollow polymeric nanoparticles for safe and effective vaccination against Middle East respiratory syndrome coronavirus,” Advanced Functional Materials, vol. 29, no. 28, article 1807616, 2019.
- C. M. Coleman, Y. V. Liu, H. Mu et al., “Purified coronavirus spike protein nanoparticles induce coronavirus neutralizing antibodies in mice,” Vaccine, vol. 32, no. 26, pp. 3169–3174, 2014.
- C. M. Coleman, T. Venkataraman, Y. V. Liu et al., “MERS-CoV spike nanoparticles protect mice from MERS-CoV infection,” Vaccine, vol. 35, no. 12, pp. 1586–1589, 2017.
- S.-Y. Jung, K. W. Kang, E.-Y. Lee et al., “Heterologous prime–boost vaccination with adenoviral vector and protein nanoparticles induces both Th1 and Th2 responses against Middle East respiratory syndrome coronavirus,” Vaccine, vol. 36, no. 24, pp. 3468–3476, 2018.
- H. Sekimukai, N. Iwata-Yoshikawa, S. Fukushi et al., “Gold nanoparticle-adjuvanted S protein induces a strong antigen-specific IgG response against severe acute respiratory syndrome-related coronavirus infection, but fails to induce protective antibodies and limit eosinophilic infiltration in lungs,” Microbiology and Immunology, vol. 64, no. 1, pp. 33–51, 2019.
- K. K. Jain and K. K. Jain, The Handbook of Nanomedicine, Springer, 2008.
- V. Manolova, A. Flace, M. Bauer, K. Schwarz, P. Saudan, and M. F. Bachmann, “Nanoparticles target distinct dendritic cell populations according to their size,” European Journal of Immunology, vol. 38, no. 5, pp. 1404–1413, 2008.
- S. Ahmad, A. A. Zamry, H.-T. T. Tan, K. K. Wong, J. Lim, and R. Mohamud, “Targeting dendritic cells through gold nanoparticles: a review on the cellular uptake and subsequent immunological properties,” Molecular Immunology, vol. 91, pp. 123–133, 2017.
- D. Raghuwanshi, V. Mishra, D. Das, K. Kaur, and M. R. Suresh, “Dendritic cell targeted chitosan nanoparticles for nasal DNA immunization against SARS CoV nucleocapsid protein,” Molecular Pharmaceutics, vol. 9, no. 4, pp. 946–956, 2012.
- T.-H. Yeh, L.-W. Hsu, M. T. Tseng et al., “Mechanism and consequence of chitosan-mediated reversible epithelial tight junction opening,” Biomaterials, vol. 32, no. 26, pp. 6164–6173, 2011.
- H.-L. Jiang, M. L. Kang, J.-S. Quan et al., “The potential of mannosylated chitosan microspheres to target macrophage mannose receptors in an adjuvant-delivery system for intranasal immunization,” Biomaterials, vol. 29, no. 12, pp. 1931–1939, 2008.
- Q. S. Sun, J. L. Zhang, D. Q. Han, Y. B. Yang, L. Zhu, and L. Yu, “Characterization and immunological evaluation of chitosan nanoparticles as adjuvants for bovine coronavirus N protein,” Applied Mechanics and Materials, pp. 113–120, 2012.
- W. W. F. Leung and Q. Sun, “Electrostatic charged nanofiber filter for filtering airborne novel coronavirus (COVID-19) and nano-aerosols,” Separation and Purification Technology, vol. 250, article 116886, 2020.
- W. W.-F. Leung and Q. Sun, “Charged PVDF multilayer nanofiber filter in filtering simulated airborne novel coronavirus (COVID-19) using ambient nano-aerosols,” Separation and Purification Technology, vol. 245, p. 116887, 2020.
- S. Yu, S. Kim, and J. Kang, “Face mask policies in South Korea in response to COVID-19,” Asia Pacific Journal of Public Health, vol. 32, no. 8, pp. 497–499, 2020.
- M. C. Sportelli, M. Izzi, E. A. Kukushkina et al., “Can nanotechnology and materials science help the fight against SARS-CoV-2?” Nanomaterials, vol. 10, no. 4, p. 802, 2020.
- M. Rai, S. D. Deshmukh, A. P. Ingle, I. R. Gupta, M. Galdiero, and S. Galdiero, “Metal nanoparticles: the protective nanoshield against virus infection,” Critical Reviews in Microbiology, vol. 42, no. 1, pp. 46–56, 2016.
- E. V. Campos, A. E. Pereira, J. L. De Oliveira et al., “How can nanotechnology help to combat COVID-19? Opportunities and urgent need,” Journal of Nanobiotechnology, vol. 18, no. 1, pp. 1–23, 2020.
- L. A. Layqah and S. Eissa, “An electrochemical immunosensor for the corona virus associated with the Middle East respiratory syndrome using an array of gold nanoparticle-modified carbon electrodes,” Microchimica Acta, vol. 186, no. 4, p. 224, 2019.
- M. Abedi, S. Z. Bathaie, and M. F. Mousavi, “Interaction between DNA and some salicylic acid derivatives and characterization of their DNA targets,” Electroanalysis, vol. 25, no. 11, pp. 2547–2556, 2013.
- S. Arca-Lafuente, P. Martínez-Román, I. Mate-Cano, R. Madrid, and V. Briz, “Nanotechnology: a reality for diagnosis of HCV infectious disease,” Journal of Infection, vol. 80, no. 1, pp. 8–15, 2020.
- Y. Fan, M. Cui, Y. Liu, M. Jin, and H. Zhao, “Selection and characterization of DNA aptamers for constructing colorimetric biosensor for detection of PBP2a,” Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, vol. 228, p. 117735, 2020.
- Z. Wu, Z.-K. Wu, H. Tang, L.-J. Tang, and J.-H. Jiang, “Activity-based DNA-gold nanoparticle probe as colorimetric biosensor for DNA methyltransferase/glycosylase assay,” Analytical Chemistry, vol. 85, no. 9, pp. 4376–4383, 2013.
- B. Maddah, V. Alimardani, and H. Moradifard, “A simple colorimetric kit for determination of ketamine hydrochloride in water samples,” Analytical Methods, vol. 7, no. 24, pp. 10364–10370, 2015.
- J. Sun, Y. Lu, L. He, J. Pang, F. Yang, and Y. Liu, “Colorimetric sensor array based on gold nanoparticles: design principles and recent advances,” TrAC Trends in Analytical Chemistry, vol. 122, p. 115754, 2020.
- E. Priyadarshini and N. Pradhan, “Gold nanoparticles as efficient sensors in colorimetric detection of toxic metal ions: a review,” Sensors and Actuators B: Chemical, vol. 238, pp. 888–902, 2017.
- Z. Zhang, H. Wang, Z. Chen, X. Wang, J. Choo, and L. Chen, “Plasmonic colorimetric sensors based on etching and growth of noble metal nanoparticles: strategies and applications,” Biosensors and Bioelectronics, vol. 114, pp. 52–65, 2018.
- M. Sastry, M. Rao, and K. N. Ganesh, “Electrostatic assembly of nanoparticles and biomacromolecules,” Accounts of Chemical Research, vol. 35, no. 10, pp. 847–855, 2002.
- E. Verveniotis, A. Kromka, M. Ledinský, J. Čermák, and B. Rezek, “Guided assembly of nanoparticles on electrostatically charged nanocrystalline diamond thin films,” Nanoscale Research Letters, vol. 6, no. 1, p. 144, 2011.
- H. Kim, M. Park, J. Hwang et al., “Development of label-free colorimetric assay for MERS-CoV using gold nanoparticles,” ACS Sensors, vol. 4, no. 5, pp. 1306–1312, 2019.
- J. C. Huang, Y.-F. Chang, K.-H. Chen et al., “Detection of severe acute respiratory syndrome (SARS) coronavirus nucleocapsid protein in human serum using a localized surface plasmon coupled fluorescence fiber-optic biosensor,” Biosensors and Bioelectronics, vol. 25, no. 2, pp. 320–325, 2009.
- M. R. de Eguilaz, L. R. Cumba, and R. J. Forster, “Electrochemical detection of viruses and antibodies: a mini review,” Electrochemistry Communications, vol. 116, p. 106762, 2020.
- F. Cui, Z. Zhou, and H. S. Zhou, “Molecularly imprinted polymers and surface imprinted polymers based electrochemical biosensor for infectious diseases,” Sensors, vol. 20, no. 4, p. 996, 2020.
- L. Rassaei, F. Marken, M. Sillanpää, M. Amiri, C. M. Cirtiu, and M. Sillanpää, “Nanoparticles in electrochemical sensors for environmental monitoring,” TrAC Trends in Analytical Chemistry, vol. 30, no. 11, pp. 1704–1715, 2011.
- U. Jarocka, R. Sawicka, A. Góra-Sochacka et al., “Electrochemical immunosensor for detection of antibodies against influenza A virus H5N1 in hen serum,” Biosensors and Bioelectronics, vol. 55, pp. 301–306, 2014.
- C. Akkapinyo, P. Khownarumit, D. Waraho-Zhmayev, and R. P. Poo-arporn, “Development of a multiplex immunochromatographic strip test and ultrasensitive electrochemical immunosensor for hepatitis B virus screening,” Analytica Chimica Acta, vol. 1095, pp. 162–171, 2020.
- C. Roh, “A facile inhibitor screening of SARS coronavirus N protein using nanoparticle-based RNA oligonucleotide,” International Journal of Nanomedicine, vol. 7, p. 2173, 2012.
- A. K. Kaushik, J. S. Dhau, H. Gohel et al., “Electrochemical SARS-CoV-2 sensing at point-of-care and artificial intelligence for intelligent COVID-19 management,” ACS Applied Bio Materials, vol. 3, no. 11, pp. 7306–7325, 2020.
- Y. Tang, C. A. Hapip, B. Liu, and C. T. Fang, “Highly sensitive TaqMan RT-PCR assay for detection and quantification of both lineages of West Nile virus RNA,” Journal of Clinical Virology, vol. 36, no. 3, pp. 177–182, 2006.
- Y. R. Chan and A. Morris, “Molecular diagnostic methods in pneumonia,” Current Opinion in Infectious Diseases, vol. 20, no. 2, pp. 157–164, 2007.
- Z. Shan, Z. Zhou, H. Chen et al., “PCR-ready human DNA extraction from urine samples using magnetic nanoparticles,” Journal of Chromatography B, vol. 881-882, pp. 63–68, 2012.
- C. Tang, Z. He, H. Liu et al., “Application of magnetic nanoparticles in nucleic acid detection,” Journal of Nanobiotechnology, vol. 18, pp. 1–19, 2020.
- Z. Zhao, H. Cui, W. Song, X. Ru, W. Zhou, and X. Yu, “A simple magnetic nanoparticles-based viral RNA extraction method for efficient detection of SARS-CoV-2,” bioRxiv, 2020.
- F.-D. Cojocaru, D. Botezat, I. Gardikiotis et al., “Nanomaterials designed for antiviral drug delivery transport across biological barriers,” Pharmaceutics, vol. 12, no. 2, p. 171, 2020.
- S. Szunerits, A. Barras, M. Khanal, Q. Pagneux, and R. Boukherroub, “Nanostructures for the inhibition of viral infections,” Molecules, vol. 20, no. 8, pp. 14051–14081, 2015.
- A. Barras, Q. Pagneux, F. Sane et al., “High efficiency of functional carbon nanodots as entry inhibitors of herpes simplex virus type 1,” ACS Applied Materials & Interfaces, vol. 8, no. 14, pp. 9004–9013, 2016.
- M. Fahmi, W. Sukmayani, S. Q. Khairunisa et al., “Design of boronic acid-attributed carbon dots on inhibits HIV-1 entry,” RSC Advances, vol. 6, no. 95, pp. 92996–93002, 2016.
- T. Du, J. Liang, N. Dong et al., “Carbon dots as inhibitors of virus by activation of type I interferon response,” Carbon, vol. 110, pp. 278–285, 2016.
- A. Łoczechin, K. Seron, A. Barras et al., “Functional carbon quantum dots as medical countermeasures to human coronavirus,” ACS Applied Materials & Interfaces, vol. 11, no. 46, pp. 42964–42974, 2019.
- S. Ye, K. Shao, Z. Li et al., “Antiviral activity of graphene oxide: how sharp edged structure and charge matter,” ACS Applied Materials & Interfaces, vol. 7, no. 38, pp. 21571–21579, 2015.
- Y. Zhou, X. Jiang, T. Tong et al., “High antiviral activity of mercaptoethane sulfonate functionalized Te/BSA nanostars against arterivirus and coronavirus,” RSC Advances, vol. 10, no. 24, pp. 14161–14169, 2020.
- C.-M. J. Hu, W.-S. Chang, Z.-S. Fang et al., “Nanoparticulate vacuolar ATPase blocker exhibits potent host-targeted antiviral activity against feline coronavirus,” Scientific Reports, vol. 7, no. 1, pp. 1–11, 2017.
- S. M. Metcalfe, “Mesenchymal stem cells and management of COVID-19 pneumonia,” Medicine in Drug Discovery, vol. 5, p. 100019, 2020.
- P. Duddu, “Coronavirus treatment: vaccines/drugs in the pipeline for COVID-19,” 2020, February 2021, https://www.clinicaltrialsarena.com/analysis/coronavirus-mers-cov-drugs/.
Copyright © 2021 Vahid Alimardani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.