key: cord-0859979-f0dpkfrs
authors: Srivastava, Manish; Srivastava, Neha; Mishra, P. K.; Malhotra, Bansi D.
title: Prospects of Nanomaterials-enabled biosensors for COVID-19 detection
date: 2020-09-16
journal: Sci Total Environ
DOI: 10.1016/j.scitotenv.2020.142363
sha: f217bac879dff36b9e37e5007a8ef4cfaf07e4c6
doc_id: 859979
cord_uid: f0dpkfrs

We are currently facing the COVID-19 pandemic which is the consequence of severe acute respiratory syndrome coronavirus (SARS-CoV-2). Since no specific vaccines or drugs have been developed till date for the treatment of SARS-CoV-2 infection, early diagnosis is essential to further combat this pandemic. In this context, the reliable, rapid, and low-cost technique for SARS-CoV-2 diagnosis is currently the foremost priority. At present reverse transcription polymerase chain reaction (RT-PCR) is the reference technique presently being used for the detection of SARS-CoV-2 infection. However, in a number of cases, false results have been noticed in COVID-19 diagnosis. To develop advanced techniques, researchers are continuously working and in the series of constant efforts, nanomaterials-enabled biosensing approaches can be a hope to offer novel techniques that may perhaps meet the current demand of fast and early diagnosis of COVID-19 cases. This paper provides an overview of the COVID-19 pandemic and nanomaterials enabled biosensing approaches that have been recently reported for the diagnosis of SARS-CoV-2. Though limited studies on the development of nanomaterials enabled biosensing techniques for the diagnosis of SARS-CoV-2 have been reported, this review summarizes nanomaterials mediated improved biosensing strategies and the possible mechanisms that may be responsible for the diagnosis of the COVID-19 disease. It is reviewed that nanomaterials e.g. gold nanostructures, lanthanide-doped polysterene nanoparticles (NPs), graphene and iron oxide NPs can be potentially used to develop advanced techniques offered by colorimetric, amperometric, impedimetric, fluorescence, and optomagnetic based biosensing of SARS-CoV-2. Finally, critical issues that are likely to accelerate the development of nanomaterials enabled biosensing for SARS-CoV-2 infection have been discussed in detail. This review may serve a guide for the development of advanced techniques for nanomaterials enabled biosensing to fulfill the present demand of low-cost, rapid and early diagnosis of COVID-19 infection.

The whole world is currently barely breathing under the shadow of the novel coronavirus . In December 2019, un-precedented pneumonia due to unknown cause was detected in the city Wuhan of China (Udugama et al, 2020; Morales-Narváez et al., 2020) .

Subsequently, on 11 February 2020, the world health organization (WHO) identified it as the new coronavirus disease-19 and it was declared as pandemic on 13 March 2020 [https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen]. The public health professionals have discovered that this new pathogen possesses about 80% similarity to the genome of the severe acute respiratory syndrome (SARS-CoV) and therefore, given the name as SARS-CoV-2 Gorbalenya et al., 2020; Lu et al., 2020) . The done through the computed tomography (CT) of the chest, and was compared to the healthy lungs, varying opacities in the CT images were recorded in the patients, leading to initial diagnosis of pneumonia (Li et al., 2020b; Bernheim et al., 2020) . Subsequently, in early January 2020 after the publication of the genetic code of coronavirus, the polymerase chain reaction (PCR) based technique was employed for the diagnosis of COVID-19 (Chu et al., 2020) .

As per the WHO guidelines, confirmation of the COVID-19 infection should be done by detecting unique ribonucleic acid (RNA) sequences of SARS-CoV-2. Further, detection of virus RNA is based on the nucleic acid amplification tests through real-time reverse-transcription polymerase chain reaction (rRT-PCR), targeting N, E, S and RdRp genes [https://apps.who.int/iris/bitstream/handle/10665/331501/WHO-COVID-19-laboratory-2020.5eng.pdf?sequence=1&isAllowed=y]. The characteristics of RT-PCR techniques (e.g. detection ability, detection limit, sensitivity, detection time etc.) towards the specific targets (R d R P gene, ORF1ab, N, S and Egene) of SARS-CoV-2 have been found to vary as per the manufacturer and compressively reviewed in recent studies [Wang et al., 2020b; Mahapatra and Chandra, 2020; LeBlanc et al., 2020; van Kasteren et al., 2020; Carter et al., 2020] . In a study by van Kasteren et al., diagnostic ability of seven different commercial RT-PCR kits for SARS-CoV-2 infection were evaluated [van Kasteren et al., 2020] . In all the assay ≥96% efficiency of PCR was noticed whereas the estimated limit of detection (LOD95) [copy/ml] exhibited 6-fold variation.

Similarly, Wang et al., observed a substantial difference in LOD of 6 commercial RT-PCR kits where the poorest LOD is estimated to be false negative result of SARS-CoV-2 diagnosis [Wang et al., 2020b] . Though the PCR-based technique relies on the RNA and is highly sensitive, there are several issues associated therein. These issues can be briefed as follows (i) complex and time-consuming, (ii) handling and transportation of samples by highly skilled staff (iii) high cost, J o u r n a l P r e -p r o o f (iii) risk to elicit false-negative and false-positive diagnosis etc. Tahamtan et al., 2020) . Further, the alternative techniques based on anti-body (serological testing) and CRISPR have been employed for the diagnosis of the SARS-CoV-2 infection (Broughton et al., 2020) .

To impede the spreading of SARS-CoV-2 among the humans and thereby reducing the mortality rate, early and fast diagnosis is the demand of the hour. Moreover, to overcome numerous issues associated with PCR-based techniques, researchers are working hard to develop the advanced and low-cost techniques to offer rapid and reliable detection of SARS-CoV-2. In this context, biosensors based on nanomaterials have been predicted to fulfill the demand of the desired fast and low-cost diagnosis techniques. Owing to interesting physicochemical properties at nano-scale, nanomaterials enabled biosensing is advantageous in several aspects e.g. (i) easy to use (ii) requirement of a very low amount of the sample analytes (iii) fast and sensitive (iv) low-cost, and easy disposability. Further, nanomaterials-enabled biosensings are being developed and have shown their potential for the diagnosis of different types of virus infectious diseases including HIV/AIDS (Farzin et al., 2020) , hepatitis B virus (Negahdari et al., 2019) , herpes virus (Narang et al., 2018) , dengue fever (Palomar et al., 2018) and influenza virus infections, etc. (Siuzdak et al., 2019; Lee et al., 2019) .

In this review we focus on the role of nanomaterials enabled biosensing techniques of different types of virus that have been considered as responsible for the onset of respiratory infections including MERS-CoV, SARS-CoV, and SARS-CoV-2. We summarize in particular the studies reported on the development of nanomaterials-enabled biosensing for the detection of SARS-CoV-2 that have been recently performed. Different types of nanomaterials such as gold based nanostructures, lanthanide-doped polysterene NPs, graphene and iron oxide NPs that have J o u r n a l P r e -p r o o f been used for the development of novel techniques for the diagnosis of SARS-CoV-2 with the help of colorimetric, fluorescence, amperometric, impedimetric and optomagnetic mediated improved biosensing have been reviewed. The emphasis has been made on the different methods for biosensing using a variety of nanomaterials and the associated mechanisms for the detection of SARS-CoV-2 infection. Moreover, future prospects to implement nanomaterials-enabled biosensing techniques for the SARS-CoV-2 infection have been discussed in detail.

SARS-CoV-2, a β-coronavirus has been identified as a single positive-strand RNA genome (Grifoni et al., 2020) . It consists of four different structural proteins namely spike (S), envelope (E), matrix (M), and nucleocapsid (N) [ Fig. 1 ]. Through the phylogenetic analysis of SARS-CoV-2, the genomic similarity about 80% and 50% have been noticed with severe acute respiratory syndrome virus (SARS-CoV) and middle east respiratory syndrome virus (MERS-CoV), respectively . More importantly, SARS-CoV-2 expresses the genomic similarity about 96% with the bat coronavirus RaTG13, and hence it is a matter of intense debate that SARS-CoV-2 may perhaps have originated from the bat . Many studies have explored that SARS-CoV-2 exploits the angiotensin converting enzyme-II (ACE2), as a receptor for the cellular entry. Further, ACE2 has been recognized for high affinity of the spike protein (S) of SARS-CoV-2 (Alifano et al., 2020). nasopharynx as the main site of replication. Nevertheless, the gastrointestinal symptoms have been noticed in anumber of patients suffering from COVID-19 (Gu et al., 2020) . Moreover, even when the nasopharyngeal sample was found to be negative, the RNA trace of SARS-CoV-2 could be detected in rectal swabs (Wang et al., 2020a; Xiao et al., 2020; Lamers et al., 2020) .

These observations clearly suggest that transmission of SARS-CoV-2 through fecal-oral is also possible. It has been reported that usually, lungs are the most affected organs by SARS-CoV-2, but other organs like brain may also be severely infected. Gandhi et al., have reported that through the olfactory bulb, the central nervous system (CNS) is most likely to be infected by SARS-CoV-2 (Gandhi et al., 2020) . Consequently, SARS-CoV-2 can easily target the thalamus and brain stem, leading to infection in the respiratory center of the brain. Thus, it ispossible that SARS-CoV-2 can infect the respiratory center of the brain and is therefore, responsible for the respiratory breakdown in patients suffering from COVID-19. Besides this, the spectrum of this disease is partly recognized in patients. And, both the symptomatic and asymptomatic cases have been noticed. In asymptomatic case, no specific symptoms have been identified. Some of the symptoms may include respiratory issues, pneumonia, fever, cough, and dyspnea (Cascella et al., 2020) . On the other hand, an asymptomatic patient is capable of transmitting this disease.

However, technically one can say that the asymptomatic individuals are more dangerous since they can spread the disease unknowingly. Therefore, the development of a low-cost and rapid diagnosis technique is imperative and is urgently needed to identify the infected patients to further prevent and control this pandemic. In this context, nanomaterials enabled biosensing approaches can be imperative and are expected to fulfill the current demand for early, rapid and low-cost point-of-care diagnostic techniques for COVID-19 detection. As discussed in the next section chemical properties of nanomaterials can be potential to design ultra-sensitive biosensing J o u r n a l P r e -p r o o f techniques for respiratory viral infections. In the meantime, to avoid the infection through SARS-CoV-2, the only options that an individual should follow are the precautionary measures [ Fig. 2 ].

Recent advancements in the field of nanobiotechnology have given birth to advanced techniques for diagnosis and therapeutic applications (Augustine et al., 2017; Palmieri et al., 2020; Malhotra and Ali., 2018; Ravina et al., 2020; Cesewski et al., 2020) . In particular,

properties of nanomaterials including high surface-to-volume ratio, quantum size effects, high adsorption and reactive capacityas compared to their bulk form are imperative to design biosensing techniques. Moreover, the size and shape of nanomaterials can be easily tailored, and, therefore, surface modification/immobilization with numerous biological species via covalent or non-covalent bonding are possible to enhance the biosensing characteristics in terms of lowdetection limit (increased up to several order of magnitudes), high sensitivity, selectivity and rapid response towards the sample analytes (Maduraiveeran et al., 2018) . Nevertheless, one of the biggest challenges in designing of biosensors (e.g. DNA/RNA) is to capture signal of very low magnitude which takes place between the biological species (bio-receptors and analytes). To overcome this issue, nanomaterials can be used as labels to achieve the significant enhancement of signal, high enough to be easily detectable. Labeling can be done using metal nanoparticles [Huang et al., 2009 ]. This LSPCF fiber-optic enabled biosensor exhibited LOD of 1 pg/mL in the human serum with a linear response, 0.1 pg/mL to 1 ng/mL. Moreover, compared to the enzyme-linked immunosorbent assay (ELISA), the LSPCF fiber-optic biosensor exhibited 10 4 -fold enhanced LOD and thus may be helpful for the early diagnosis of SARS infection. And it is anticipated that using such fiber optics based nanoenabled biosensing can detect the viral load as small as 10 6 particles/mL within 15 min [Murugan et al.; Nag et al.; . These studies suggest that nanomaterials-enabled biosensing can be potential approach for the early and rapid detection of the virus originated respiratory infections.

Owing to exceptional physicochemical properties, gold-based nanostructures have been widely employed for biomedical applications. Particularly, gold nanostructures have been exploited as the signal transducers in terms of optical signal amplifier, current amplifier, and J o u r n a l P r e -p r o o f resonance light scattering to fabricate biosensors for virus detection (Draz et al., 2018) . A unique dual-functional biosensing platform based on plasmonic effect for the sensing of SARS-CoV-2 has been developed by Qiu et al. (Qiu et al., 2020) . The developed biosensor exploits the combination of plasmonic photothermal (PPT) and the localized surface plasmon resonance (LSPR) effect. This biosensor was designed using two-dimensional gold nano-islands (AuNIs)

[2D-AuNIs] chip following the self-assembly of thermally de-wetted gold (Au) nanofilm on the BK7 glass surface, wherein the Au-film was firstly prepared by magnetron-sputtering. sensitive. On the other hand, ELISA kit showed a sensitivity of 87.3%. Moreover, both the GICA and ELISA kits were 100% specific in case of normal patients and no significant difference between these two kits could be noticed. This study suggests the feasibility of colloidal gold NPs to prepare immuno-chromatographic kit that may assist to relieve huge pressure of the clinical diagnosis of COVID-19 cases through rRT-PCR based technique. rabbit IgG (R-IgG) following EDC/NHS chemical reaction. A nitrocellulose membrane was used as the template to immobilize a recombinant nucleocapsid phospho-protein of SARS-CoV-2, responsible to confine the specific IgG. Fig. 6 Thus, the authors affirmed that though the developed LFIA did not yield accurate quantitative results due to non-availability of any anti-SARS-CoV-2 IgG standard, it can be of high interest for rapid diagnosis of the suspicious COVID-19 cases .

Graphene, 2D hexagonally arranged carbon based single atom thick layer has proven its worth towards the development of advanced biosensing platforms (Li et al., 2020a) . This is mainly because of numerous exceptional properties such as high specific surface area, high electrical, and ionic mobility; thus, it has the potential to develop ultrasensitive biosensors (Peña-Bahamonde et al., 2018) . By exploiting these properties of graphene, Seo et al. developed a fieldeffect transistor (FET) based biosensing platform to detect SARS-CoV-2 in human nasopharyngeal swabs (Seo et al., 2020) . The FET-based biosensing platform was developed by transferring graphene onto the SiO 2 /Si substrate following the wet-transfer method.Further, this graphene based-FET device was possible to develop by using the photolithography technique.

Subsequently, the graphene surface was coated with a specific antibody of SARS-CoV-2 spike J o u r n a l P r e -p r o o f protein to finally prepare the FET-based biosensing device. The clinical application of the FETbased biosensing device was investigated using different sample analytes e.g. antigen protein, cultured virus, and nasopharyngeal swab of COVID-19 patients. Detection of SARS-CoV-2 spike protein was measured at the concentration of 1 fg/mL in phosphate-buffered saline whereas 100 fg/mL in case of the universal transport medium.This graphene-based FET sensor exhibited LOD, 1.6 × 10 1 pfu/mL, and 2.42 × 10 2 copies/mL in case of SARS-CoV-2 spiked culture and clinical samples, respectively [ Fig. 7 ]. It may be noted that there was no measurable interference that could be detected with MERS-CoV antigen, suggesting practical application for diagnosis of COVID-19 patients (Seo et al., 2020) .

Magnetic nanoparticles (MNPs) have emerged as promising candidates to develop biosensors for the detection of the deadly respiratory viral infections [Islam and Ahsan, 2020; Barnett et al., 2020] . Using MNPs different biosensing techniques have been developed such as magnetic resonance (NMR/MRI) [Perez et al., 2003] , fluorescence , electrochemical [Khan et al., 2020] , and rolling circle amplification [Tian et al., 2020a; Tian et al., 2020b] . . The pcMNPs based nano-system exhibited the combined properties including virus lysis and RNA binding in a single step. Thus, resulting pcMNPs-RNA complex could be directly used for the subsequent RT-PCR reactions. Further, with the identification of ORFlab and N gene of the viral RNA, the pcMNPs enabled RT-PCR based biosensing was found to be 10-copy sensitive, and having a linearity of 10-10 5 copies of the SARS-CoV-2 pseudovirus particles. This study suggests that the pcMNPs-enabled RNA extraction approach can be a promising alternative to overcome issues in the rapid diagnosis of SARS-CoV-2 through RT-PCR based technique. Table 1 summarizes the characteristics of the nanomaterials-based biosensors, reported for SARS-CoV-2 detection.

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

The pandemic of COVID-19 has motivated researchers tomake efforts towards the development of an advanced approach that must be highly efficient and should be capable of responding to the present demand of early diagnosis to manage this global issue. Since there is no explicit technique currently available for the treatment of COVID-19, therefore the management of this pandemic is only possible through detection, monitoring, and prevention of SARS-CoV-2 infection in time. Moreover, the asymptomatic cases of COVID-19 have made this issue more complex and, therefore, it is necessary to invent a rapid and low-cost technique for the early diagnosis of this suspicious infection at mass levels to discriminate against the infected and non-infected cases. In this context, since the nanomaterials-based biosensors have already shown their potential towards the diagnosis of numerous viral infections and hence may perhaps fulfill the current demand for early diagnosis of COVID-19 cases. And it appears that different types of nanostructures such as gold, lanthanide-doped polysterene NPs, graphene and IONPs could be successfully employed for the development of advanced biosensing techniques for the diagnosis of SARS-CoV-2. Besides, using these NPs, a number of methods including amperometric, impedimetric, colorimetric, magnetic and optomagnetic mediated biosensing have been established. These methods can be utilized to detect the SARS-CoV-2 within 10 min to 100 min and therefore may assist in the early and rapid diagnosis of COVID-19 cases. Though, limited studies on the development of nanomaterials-based biosensors for SARS-CoV-2 detection have been reported, these nanomaterials enabled biosensing techniques offer alternative approaches to PCR-based testing for COVID-19 infection. Moreover, under the outbreak of COVID-19, these nanomaterials-based biosensing can be imperative to deliver the requirement of easy, low-cost, rapid and real-time diagnosis technique. Thus, the nanomaterialsbased biosensing is likely to reduce the stress on RT-PCR-based costly testing of COVID-19 J o u r n a l P r e -p r o o f cases. Further, byemploying nanomaterials based biosensing devices as plug-and-play diagnostics approach are expected to be highly useful to fight against this pandemic.

It is predicted that the reported nanomaterials-enabled biosensors mainly rely on nucleic acid (RNA/DNA) and protein (antigen/antibody) mediated detection of SARS-CoV-2. Nevertheless, these techniques have not yet yielded 100% accuracy owing to the contamination of these highly sensitive bioreceptors. And even a single false result would be highly challenging and can spoil the efforts to overcome this pandemic. Thus, other alternatives including nanomaterials-mediated biosensing technique based on CRISPR can perhaps be explored to detect SARS-CoV-2 should be investigated (Lucia et al., 2020) . In particular, nanomaterials -based biosensors that rely on the aerosol mediated diagnosis approach can be significant and are likely to offer numerous advantages e.g. fast response, sensitivity, as well as lack in sampler perturbation (Huffman et al., 2020) . Besides, this, at lab-scale it is possible to achieve a low detection limit, good stability, and Finally, since only a few studies have been performed on the applications of nanomaterialsenabled biosensing for SARS-CoV-2, we are at very early stage of the nanomaterials-enabled biosensing technology. Therefore, efforts should be made to advance this approach to harvest the rich dividend in the near future to combat the battle against COVID-19 pandemic. (v) dual-functional plasmonic photo-thermal biosensors for SARS-CoV-2 using AuNIs [Qiu et al., 2020] . (vi) optical fiber enabled biosensing [Nag et al., 2020] , (vii) realtime optomagnetic detection of SARS-CoV-2 following homogeneous circle-to-circle amplification [Tian et al., 2020b] nasopharyngeal swabs FET based biosensing device could detect the SARSCoV-2 spike protein at concentrations of 1 fg/mL in phosphate-buffered saline and 100 fg/mL in clinical transport medium; Limit of detection: 1.6 × 10 1 pfu/mL in culture medium whereas 2.42 × 10 2 copies/mL in clinical samples [Seo et al., 2020] J o u r n a l P r e -p r o o f 

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