key: cord-0726738-6vmajhhj
authors: Allawadhi, Prince; Singh, Vishakha; Khurana, Amit; Khurana, Isha; Allwadhi, Sachin; Kumar, Pawan; Banothu, Anil Kumar; Thalugula, Sunitha; Barani, Percy Jasmine; Naik, Ramavath Redya; Bharani, Kala Kumar
title: Silver nanoparticle based multifunctional approach for combating COVID-19
date: 2021-06-02
journal: Sensors international
DOI: 10.1016/j.sintl.2021.100101
sha: 4ee8c8e7f2844e0a56801752329888760c8ef6d6
doc_id: 726738
cord_uid: 6vmajhhj

COVID-19 is a highly contagious and widespread disease that has strained the global healthcare system to the hilt. Silver nanoparticles (AgNPs) are well known for their potent antimicrobial, antiviral, immunomodulatory, and biosensing properties. AgNPs have been found to be potential antiviral agent that acts against many deadly viruses and is presumed to be effective against COVID-19. AgNPs can generate free radicals and reactive oxygen species (ROS) leading to apoptosis mediated cell death thereby inhibiting viral infection. The shape and size of AgNPs play an important role in its biomedical applications as alterations may result in variable biological interaction and activity. Herein, we propose that AgNPs can be utilized for the effective management of the ongoing COVID-19 pandemic by highlighting the current status of AgNPs in the fight against COVID-19.

In December 2019, in Wuhan city of China, a cluster of pneumonia cases similar to the severe acute respiratory syndrome (SARS) were reported, which was caused by a newly discovered strain of coronavirus (CoV) [1] . Subsequently, the disease was named COVID-19, and the virus involved in this disease was designated as SARS-CoV-2 [2] . Coronaviruses comprises of a big class of viruses that consists of a core of genetic material (single-stranded RNA genome) enveloped by a spherical lipid layer with spikes like protein structure attached to the surface.

This structure gives it a crown-like appearance, and in Latin, corona means crown, so this is why, these viruses are labelled as coronaviruses [3, 4] . The genomic sequence of this new virus is 78.5%, similar to that of the previously known SARS-CoV. However, SARS-CoV-2 transmits faster than SARS-CoV [5] [6] [7] . The SARS-CoV-2 virion contains structural proteins namely spike, envelope, membrane, and nucleocapsid protein. The RNA genome of the virion is encapsulated by the nucleocapsid, while membrane and envelop protein in assembly process confirm its incorporation into the viral particle. Spike protein has specificity towards the host entry receptors i.e., the spike protein interacts with the host angiotensin-converting enzyme 2 (ACE2), alongwith host factors like cell surface serine protease TMPRSS2 which stimulates uptake and fusion of the virus at host cellular membrane [8] . [9, 10] . Currently, most of the treatments for COVID-19 management are given for symptomatic relief and support the respiratory system of seriously ill patients [11, 12] . Though, the Sputnik-V and BNT162b2 vaccines have been granted rapid clinical approvals, their safety remains unclear and the recent complications including the disputed cases of Bell's palsy with BNT162b2, indicate the enormity of risk involved in approving vaccines in a haste [13] [14] [15] . The need of present time is to develop and design potent antiviral agents that may aid in fighting and overcoming the COVID-19 pandemic [16] [17] [18] .

J o u r n a l P r e -p r o o f Metals including calcium, iron, selenium and zinc play a crucial role in a number of vital biochemical reactions which are essential for growth and survival [19] [20] [21] . Though, silver (Ag) is not an essential element, it is an important element of biomedical importance. Nanoparticles (NPs) are well known for their numerous advantages including increased surface area, tailored release profile of the cargo, modulation of drug pharmacokinetics, reduced toxicity and improved biological response [22, 23] . AgNPs are considered as one of the potential therapeutic nanoparticles and are included in most commercialized NPs considering their distinctive catalytic, optical and clinical applications. AgNPs can induce immunologic response and cause inflammatory cell apoptosis in the host. Silver is used in a significant number of Ayurvedic formulations including fortified Chyavanprash and Bhasmas. Further, it has been reported to be beneficial against a variety of inflammatory, cardiovascular and other non-communicable disorders [19, [24] [25] [26] [27] . Silver possesses potent antimicrobial and immunomodulatory effects and its nano form has been reported to attenuate the progression of multiple diseases including diabetes [28] . Some of the marketed products based on silver are PolyMem Silver™ (Aspen), Acticoat™ and Bactigras™ (Smith & Nephew), Tegaderm™ (3M) and Aquacel™ (ConvaTec)

[29]. cells. Smaller size AgNPs were reported more effective [42] . Further, AgNPs decorated with silica elicit potent antiviral effects against influenza A virus (IFV-A) by modulating the viral membrane protein that inactivates the IFV-A [43] . AgNPs show antiviral effects against hepatitis B virus by interacting with dsDNA or by attaching to viral bodies and halt their pathogenic characteristics [44, 45] . In a recent work, AgNPs (2-15 nm) were reported to inhibit extracellular SARS-CoV-2 at a concentration as low as 1 ppm. It was reported via a luciferase based pseudovirus entry assay where AgNPs prevented the virus entry inside the host cell by disturbing viral integrity [36] . AgNPs blocked the binding and stopped the penetration of monkey pox virus J o u r n a l P r e -p r o o f in host cells, making them inefficient to replicate [46] . Furthermore, AgNPs coated with polyvinylpyrrolidone (PVP) interfere with respiratory syncytial virus and herpes simplex virus to inhibit their attachment to the cellular membrane rendering them incapable of infection [47, 48] . Table 1 enlists the antiviral effects of AgNPs. Taken together, these reported findings demonstrate that AgNPs can contribute a considerable role in confrontingCOVID-19 pandemic.

Severe inflammation and lung fibrosis are the typical hallmarks of the patient suffering from COVID-19. Cytokine storm causes the induction of systemic as well pulmonary inflammation by driving the pro-inflammatory signaling which is also involved in lung fibrosis [17, 49, 50] . In this context, AgNPs can be a promising therapeutic candidate having potential anti-inflammatory and anti-fibrotic properties by virtue of its capability to abrogate the inflammatory cytokines by 

AgNPs have been referred to as a convincing therapeutic NP possessing potent immunomodulatory features. Since ages, silver is used as a health supplement in Ayurvedic system of medicine to boost immune system and to strengthen the vital functions of body.

AgNPs are known to induce immunogenic response within the biological hosts, together with the immune cells [55] . Bhol et al., reported that AgNPs induce the downregulation of IL-12 and TNF-α by promoting apoptosis in inflammatory cells [56] . gamma (IFN-γ) and more weakly, IL-5 [58, 59] . It has also been reported that AgNPs can remarkably reduce the load of viral infection by inhibiting nuclear translocation of NFκB [60] .

Moreover, the extended intravenous administration of AgNPs of size 20 nm or 100 nm in rats exhibit several immunomodulatory effects such as declining body weight, enhanced spleen weight and size, and an inclination in both B cell and T cell count in spleen. However, high doses of AgNPs result in overall repression of natural killer (NK) cells activity, halting IL-10 and IFN-γ synthesis by spleen cells, enhanced IL-1β and decline in IL-6, IL-10 and TNF-α by spleen cells, upregulation of IgM and IgE in serum and an enhancement in blood neutrophilic granulocytes [61] . Additionally, the administration of AgNPs orally leads to suppression of proliferation of lymphocytes while promotes phagocytosis alongwith causing respiratory burst of monocytes and granulocytes [62] . Additionally, the intratracheal delivery of AgNPs in mice subsequently results in enhanced neutrophil counts and IL-1β levels. The exposure of 24, 48 or 72 h AgNPs lead to decline in the murine macrophage cell viability and a remarkable decrease in nitric oxide (NO) production was also observed [63] . It has been observed that murine macrophage exposure to AgNPs in vitro leads to significant decrease in cell viability with an observation of intracellular localization disclosing the distribution of Ag generally to high molecular weight proteins, and AgNPs colocalization with lysosomes. This study suggests that AgNPs are internalized by macrophages and transferred to the lysosomes where they induce inflammatory response [64] . The immunomodulatory effect of AgNPs is also dependent on size as seen in Raw 264.7 murine macrophages, where NPs of 20 nm diameter were found to stimulate ROS production, apoptotic cell death, decline in metabolic activity and generation of IL-6, IL-1β, IL-1α, G-CSF, TNF-α, MIP-2, MIP-1a and MIP-1b, then 80 nm or 113 nm diameter AgNPs [65] . Additionally, the size dependent effect of AgNPs was shown in human macrophages utilizing cDNA microarray analysis where 5 nm AgNPs leads to more potent proinflammatory cytokines and stress gene expression compared to the 100 nm AgNPs [66] .

Similarly, the effect of 20 nm and 110 nm AgNPs has been examined in several epithelial cell lines and macrophages. It was found that 20 nm NPs were more destructive to both the cell lines because the smaller particles are easily dissolved in acidic phagolysosomes, that is accordant J o u r n a l P r e -p r o o f with silver induced toxicity [67] . Thus, AgNPs can be utilized as an adjuvant therapy in current treatment regimen to boost the immunity of COVID-19 patients.

To combat the battle against COVID-19, biosensors will play a pivotal role [68] . Currently, many biosensors are being developed for COVID-19 detection. Most of them are based on the antibodies detection by different types of assays, such as enzyme-linked immunosorbent assay (ELISA) and real time -polymerase chain reaction (RT-PCR). But these kits are expensive and time consuming. Further, in some cases, these kits give false-positive results. So, it is required to develop highly accurate, sensitive, and affordable sensors for early-stage diagnosis of COVID-19 [69] . AgNPs-based biosensors could be utilized in diagnostics and detection of viral infections precisely [70] . AgNPs can also be useful to reduce the impact and burden of disease by providing simple, faster and ready to use systems that do not need specific equipment and trained manpower [71] . AgNPs containing paper-based colorimetric DNA sensors for the detection of J o u r n a l P r e -p r o o f 

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