Finding a solution by any means to stop the COVID-19 outbreak in this urgent scenario would be an applaudable step. The global scientific community is struggling to develop sprint technologies to fight this pandemic (Rai et al., 2020). Because of their exceptional properties and biocompatibility, carbon dots can be investigated as a promising solution in the pursuit of an effective therapeutic strategy against COVID-19 (Garg et al., 2020). Exploring these nanostructures for specific and tailored functions is in need to provide solutions for exigencies like COVID-19. Carbon dots have shown proven antiviral effects and that too against Coronaviruses (Du et al., 2018; Ting et al., 2018). At present environment-friendly carbon dots are available for various applications (Du et al., 2014; Park et al., 2014; Yuan et al., 2016). The existence of nanosized functional substances in natural systems has captured a great curiosity for the scientific community due to their unique properties.

Every year millions of people are killed by viral infections and nearly one-third of global mortality is due to infectious diseases. And now the new emerging viral diseases like COVID-19, SARS, MERS, etc. add on to this. Even though vaccination is the best approach to prevent this pandemic situation, unfortunately, it is not yet practical for newly emerging infections. Nanotechnology has tremendous potential in different areas to fight against COVID-19, which include diagnosis, prevention as well as treatment. The application of nanotechnology in antiviral therapy is still in its early stages (Borah et al., 2020; Chen and Liang, 2020; Innocenzi and Stagi, 2020; Palmieri and Papi, 2020). Constant emergences of novel viruses are challenging and need more attention in research on nanotechnology-based targeted antiviral therapy. In this review, we are focusing on the potential therapeutic applications of carbon dots against COVID-19. Once infected with SARS-CoV-2 the patients may need treatment to stop the replication of the virus inside the body. The mechanism of SARS-CoV-2 infection has been already reported in the literature (Coperchini et al., 2020; Dhama et al., 2020; Li et al., 2020; Wang et al., 2020). Reports suggest that the SARS-CoV-2 virus binds to the angiotensin converting enzyme 2 (ACE2) receptor with its spike protein and the virus is around 60–140 nm in size (Chan, 2020). These two findings can be exploited for the design and development of potential tools for the treatment based on nanotechnology. There are several studies done on viral research based on nanotechnology which proves the powerful ability of nanoparticles as antiviral agents. Moreover, functionalized nanoparticles have been proved for its extremely powerful inhibition on proliferation of viruses (Chen and Liang, 2020). Out of these, carbon dots are gaining special interest owing to their exceptional cell membrane permeability, biocompatibility, low cytotoxicity, and functionalization property (Wang and Hu, 2014; Georgakilas et al., 2015; Lim et al., 2015). Carbon dots or carbon quantum dots are now an emerging group of carbon nanoparticles with <10 nm in size and luminescent property (Molaei, 2019). Xu et al. found this luminescent carbon for the first time in 2004 while purifying single-walled carbon nanotubes (Xu et al., 2004). Since carbon dots have several desirable properties like low cytotoxicity, biocompatibility, inertness, photostability, easier synthesis, and functionalization, etc. these are gaining more research interests since its discovery (Zuo et al., 2016; Al-Qattan et al., 2018; Mahajan et al., 2018; Maheshwari et al., 2019; Tian et al., 2020). Apart from drug delivery or therapeutic applications they are well-established for in vitro as well as in vivo bio-imaging, chemiluminescence, optical sensing, photocatalysis, etc. They are also well-known for their low or no cell toxicity and biocompatibility. Zebrafish larvae showed a normal growth after treating with 1.5 mg/mL carbon dot solution (Kang et al., 2015). Moreover, HeLa cell viability (more than 90%) was observed after incubation of 24 h with 500 μg/mL of carbon dots and the observed LC₅₀ was above 5 mg/mL (Ding et al., 2013). Several researches have proved the non-toxicity and safety of carbon dots for in vivo applications in animal models. Neutral carbon dots are more promising for biological applications since they do not induce any cellular abnormalities. Negatively charged carbon dots may induce oxidative stress and positively charged carbon dots may be cytotoxic also (Wang K. et al., 2013; Havrdova et al., 2016; Emam et al., 2017). Poor stability and difficult to maintain properties for longer periods of time are another limitations of these nanosized carbon particles (Mishra et al., 2018). The regulatory concerns are similar to nanoparticles. To focus on the regulatory issues on nanoparticles, European Medical association have already created an expert group on nanomedicines. A new concept, Safe-by-Design concepts can be used to anticipate the risk identification, reduction and ambiguities regarding human health and environmental safety in early stages of nanotechnology related product development (Schmutz et al., 2020).

Extensive research have been done by many scientists to prove the ability carbon dots in photodynamic therapy, cancer therapy, antimicrobial therapy etc. (Hola et al., 2014; LináChee and JunáLoh, 2015; Bing et al., 2016; He et al., 2018; Li et al., 2018). A recent review by Basak et al., also gives the potential of carbon dots against viral infections briefly along with some other potential nanomaterials (Basak and Packirisamy, 2020). A large number of reviews are published recently mentioning the potential and possibilities of nanomaterials to fight against corona virus (Innocenzi and Stagi, 2020; Manivannan and Ponnuchamy, 2020; Mukherjee et al., 2020; Nair et al., 2020). But our review focus on the possibility of carbon dots and also functionalized or doped carbon dots against viral infection with special emphasis to corona virus.

Different approaches have been developed for the production of carbon dots, which are mainly categorized as top-down and bottom-up approaches. Some of the most widely used methods include hydrothermal synthesis, pyrolysis, microwave-assisted synthesis, electrochemical oxidation, laser-ablation, etc. from a different diversity of carbon sources (Lim et al., 2015). Some of the precursor molecules for bottom-up approach include ethylene glycol (Hu et al., 2013), boric acid/glycine (Jahan et al., 2013), ethylenediamine and citric acid (Fahmi et al., 2016; Łoczechin et al., 2019) and various green sources like apple juice (Mehta et al., 2015), bee pollen (Zhang et al., 2015), cabbage (Alam et al., 2015), carica papaya juice (Kasibabu et al., 2015), garlic (Zhao S. et al., 2015), ginger (Li et al., 2014), Grape peel (Xu et al., 2015), grass (Liu et al., 2012), honey (Yang et al., 2014), milk (Wang and Zhou, 2014), etc., whereas candle soot (Liu et al., 2007), lampblack (Wang X. et al., 2013), graphite (Anilkumar et al., 2011), etc. are examples of some of the precursor compounds for top-up approach. After synthesis or during synthesis, modification can be achieved by techniques like surface passivation (Zhu et al., 2009; Lai et al., 2012), inorganic salt doping (Anilkumar et al., 2011) and element doping (Dong et al., 2012; Jiang et al., 2012). Surface passivation and functionalization further expand their exploitation from biosensing to drug delivery. For green carbon dots, doping or excessive surface passivation is not necessary since these are almost self-passivated during the nucleation process (Miao et al., 2016).

This review article is exploring the potentials and possibilities of carbon dots against SARS-CoV-2 based on the published research data on antiviral activity of carbon dots. There are not much research done on the applicability of carbon dots against corona virus especially SARS-CoV-2 virus. But the article details all the possible mechanisms by which carbon dots can act against virus and especially corona virus. This review is not detailing the properties, synthesis, and other applications of carbon dots since these are extensively discussed in many reviews (Baker and Baker, 2010; Zhao A. et al., 2015; Yuan et al., 2016; Jaleel and Pramod, 2018). We anticipate that this review article would offer precious insight and cheer up the scientific community for a deeper exploration of therapeutic and diagnostic applications of carbon dots against SARS-CoV-2.

Carbon nano-dots act by a different mechanism at different stages of viral replication. The mechanism of viral infection generally involves four main steps namely attachment, penetration, replication, and finally budding.

In a recent article by Garg et al., elaborated the inhibitory mechanism of human coronaviruses by hetero atom doped carbon dots. The research group propose the potential development of triazole-based carbon dots against SARS-CoV-2 infection using a series of bioisosteres. Since carbon dots have a large number of hydrophilic functional groups on borders, they are appropriate for diverse biomedical applications. In addition to this the surface functionality of these magic nano substance is vital to fine-tune the of interaction level with virus (Garg et al., 2020).

Curcumin cationic carbon dots (CCM-CDs) can efficiently inhibit coronavirus infection. Curcumin carbon dots were synthesized by the hydrothermal reaction of curcumin and citric acid in a Teflon coated autoclave followed by purification with centrifugation and then dialysis. The CCM-CDs were found to inhibit the entrance of virus, production of the negative strand of RNA as well as budding. Suppression of viral replication was found to be due to stimulation in the production of interferon stimulating genes as well as pro-inflammatory cytokines and also due to the accumulation of ROS. This was proved as a multisite inhibitor for Enteric Coronavirus (Figure 2). This one step ultrasmall sized (1.5 nm) antiviral fluorescent CCM-CDs with a positive charge and many hydrophilic groups obtained by pyrolysis of curcumin are highly effective against coronavirus model (porcine epidemic diarrhea virus) (Ting et al., 2018).

Carbon dots can effectively inhibit the replication of RNA viruses like Porcine reproductive and respiratory syndrome viruses. Carbon dots are synthesized by the hydrothermal reaction of PEG-diamine and ascorbic acid in a Teflon coated autoclave chamber. The antiviral activity was tested in vitro on Monkey kidney cells infected with Porcine reproductive and respiratory syndrome viral strain, WUH3. Viral replication is inhibited by increased interferon-α production and enhanced expression of interferon-stimulating genes (Du et al., 2016). A broad strategy of anti-coronavirus therapy is not practically possible due to the biodiversity and rapid mutation characteristic of coronaviruses. Loczechin et al. developed seven different types of carbon quantum dots against human coronavirus. The first generation carbon dots were made from ethylenediamine/citric acid by hydrothermal carbonization and then functionalization was carried out by chemical integration of boronic acid. The second-generation carbon dots were prepared from 4-aminophenyl boronic acid. Inhibition of HCoV-229E entry as well as viral replication was achieved with the developed carbon dots (Łoczechin et al., 2019). Boronic acid or amine group surface functionalized carbon dots can inhibit type 1 herpes simplex virus infections. The carbon dots were synthesized from 4-aminophenyl boronic acid hydrochloride by hydrothermal carbonization showed a high potency to prevent the infection in herpes simplex type 1 infected A549 and Vero cells. The research showed that the carbon dots interfere with the entry of the virus into the host cell (Barras et al., 2016). Carbon dots derived from benzoxazine monomers by hydrothermal reaction was found to be effective against the adenovirus-associated virus, porcine parvovirus, dengue virus, Zika virus, and Japanese encephalitis virus. Carbon dots were formed as a result of pyrolysis, carbonization, and oxidization of benzoxazine monomers in the presence of aqueous sodium hydroxide (NaOH) in a Teflon coated stainless steel autoclave. These carbon dots were able to bind directly to viral surface proteins and stop the first step of vial attachment with the host cells (Huang et al., 2019).

Curcumin derived carbon quantum dots were found to be effective against enterovirus 71 also. One-step heating at a temperature of 180°C preserved polymeric curcumin moieties with advanced antiviral properties. The core-shell of carbon dots is formed by dehydration, polymerization, carbonization, and surface passivation of curcumin with pyrolytic curcumin like polymer surface, polymerization, crosslinking carbonization, and surface passivation. Insoluble black carbon materials are formed as a result of severe pyrolysis as well as carbonization of curcumin at higher temperatures. In this reaction, curcumin acts both as a source of carbon and also as a source of surface functionalization moiety. In new born mice infected with a lethal dose of enterovirus 71, this curcumin derived, biocompatible carbon dots was able to decrease mortality and protects from virus-induced paralysis of the hind limb. The antiviral effect is due to the inhibition of viral attachment, promotion of antioxidant action, and also the alteration of transcription regulation, activation of intracellular signaling cascades (Lin et al., 2019). Surface modified carbon dots were able to produce a significant antiviral effect on human norovirus virus-like-particles (VLP) by inhibiting binding to histo-blood group antigen receptors on human cells. In this work, chemical functionalization was carried out on harvested carbon nanoparticles from the commercially available carbon nano powders. The 2,2′-(ethylenedioxy)-bis(ethylamine) (EDA) functionalization was achieved by refluxing carbon nanoparticles with thionyl chloride and mixing with dried EDA liquid under heat and nitrogen environment. EDA carbon dots were separated after centrifugation and dialysis against water. It was found that the carbon dots were able to inhibit the binding of human norovirus virus-like particles to saliva A, B, and O type HBGA receptors. It could also inhibit VLPs' binding to their corresponding antibodies. The study could prove the antiviral property of carbon dots by inhibiting the binding of viruses with HGBA receptors. The paper points out that this strategy could be effectively used in preventing or spreading of human Norovirus infection since there is no effective vaccine. The strategy of disabling viral recognition of binding sites on host cells can be used as a promising antiviral approach (Dong et al., 2017).

Highly biocompatible carbon dots from glycyrrhizic acid were able to inhibit the entry as well as reproduction of porcine reproductive and respiratory syndrome virus. These carbon dots were produced by hydrothermal process by the addition of NaOH in a Teflon-lined autoclave. These carbon dots possess the ability to inhibit the accumulation of ROS in the cell as well to stimulate the innate immune response. Moreover, it could inhibit porcine epidemic diarrhea virus and pseudorabies virus which suggests its broad spectrum of antiviral activity (Tong et al., 2020).

Du et al., developed Glutathione capped CdTe quantum dots against pseudorabies virus. From the growth curve as well as fluorescence co-localization analyses it was clear that CdTe QDs inhibit viral multiplication at an early stage by controlling the invasion, and also found that it has no significant action against viral penetration. The size of quantum dots decreased gradually by addition of virus within 30 min due to the of release Cd²⁺ by interaction with the virus and as result a reduction in the number virus which can infect cells was achieved. The structure of viral surface proteins is also altered was evidenced by Raman spectra and Circular Dichroism spectroscopy analyses. This research gives an in-depth understanding of the inhibition of viral pathogenesis by carbon dots (Du et al., 2015).

Liu et al. developed two types of carbon dots by a hydrothermal process which can selectively enter into the cytoplasm and the whole cell with no surface modification. Blue-fluorescent carbon dots were prepared by heating powdered young barley leaves with anhydrous citric acid in a stainless steel autoclave. Cyan-fluorescent carbon dots were produced in a similar way as the previous one with the addition of urea along with citric acid. The carbon dot with blue fluorescence can only enter the cytoplasm but with comparatively better antiviral property against pseudorabies virus, while the cyan-fluorescent carbon dot was cable of distribution over the entire cell, including the nucleus (Liu et al., 2017).

Quantum dots prepared by using microwave were able to inhibit viral replication both in vivo and in vitro by the inhibition of cellular nuclear factor κB signaling pathway. This pathway has a vital role in the inflammatory response. The carbon dots were prepared similar to their previous work by microwave synthesis of aqueous dispersed CdTe/CdS/ZnS Core-Shell-Shell procedure which produced biocompatible and photostable carbon dots. Apart from antiviral activity, the carbon dots exhibited anticancer and anti-inflammatory activity (Hu et al., 2016).

Carbon dots can successfully prevent HIV 1 infection through inhibition of target cell interaction by interfering with the entry step. Carbon dots are synthesized by citric acid pyrolysis and functionalized with boronic acid since it ensures the specific interaction of carbon dots with glycoprotein on the viral surface. This boronic acid conjugated carbon dots was able to bind to gp120 protein on the virus and stop the binding of MOLT-4 cells and block infection. In vitro experiments proved that higher concentrations of boronic acid conjugated carbon dots on syncytia, which mediate fusion of infected cells with an adjacent cell, were observed in the cultured cells. The absence of cellular toxicity is proved on MOLT-4 human leukemia cells by specific assays. The results offer a basis for the advanced exploration of functionalized carbon dots in antiviral therapy (Fahmi et al., 2016). The published researches on carbon dots for the antiviral effect are summarized in the Table 1.

Polyamine-modified carbon quantum dots were proved to inhibit White spot syndrome virus infection by attaching to the viral envelope in a dose-dependant manner (Huang et al., 2020). Carbon dots were synthesized by direct pyrolysis by heating of spermidine powder (Jian et al., 2017). This virus causes white spot syndrome in cultured shrimps which has led to high mortality rates in culture shrimps around the globe. The viral inhibitory effect of this polyamine capped carbon dots was confirmed through in vivo experiments (Huang et al., 2020).

The above mentioned are the published researches which proved the excellent ability of these carbon derived nano-substances as antiviral agents. Works mentioning the antiviral activity of simple carbon dots as well as surface functionalized carbon dots were discussed. In most of the research mentioned here the antiviral activity is by one or more mechanism which affect the life cycle of virus. From these results we can understand that carbon dots derived from natural antiviral agents like curcumin has excellent ability against corona virus. It should be noted that surface modification or functionalization also improved the antiviral activity of carbon dots.

In this current review, we have addressed all the published research as well as review articles on antiviral carbon dots along with a brief description of the synthesis and its antiviral mechanism of action. Therefore, carbon dots have proved promising application against different types of corona viruses. Still, more focus required to be given in exploring carbon dot-based antiviral agents for treating SARS-CoV, MERS-CoV, and SARS-CoV-2 viral infections. Carbon dots are extensively researched in biomedicine other than therapy like biosensing, bioimaging, etc. Surface functionalization and low toxicity makes carbon dots the most superior among other nanoparticulate therapeutic delivery systems. These functionalized carbon dots can stay as a new stage for the production of biosafe nanotherapeutics for treating viral infections in the near future. Among the reviewed researches carbon dots derived from herbal sources like curcumin, glycyrrhizin, etc. was found to be more promising because of their biocompatibility, lower toxicity, and strong in vitro as well as in vivo antiviral activity.

Apart from this, carbon dots could probably be exploited in many other ways. As there is no specific vaccine against SARS-CoV-2, cleaning of contaminated surfaces and handwashing are highly needed to prevent the spread of disease. Therefore, incorporation of carbon dots to sanitizing solutions, handwashing soaps, cleaning detergents, etc. will be useful. Carbon dot incorporated masks and air filters also seem to be promising.

What we suggest from these studies is that a bottom up approach with natural antiviral agent as a precursor for the production of carbon dots will be a promising option. Additional surface passivation/functionalization can also be considered for enhancing the efficiency. Carbon dots with positive charge and more hydrophilic groups on surface will be an add-on for a superior anti-viral action.

Regardless of the encouraging results, still much more research is needed to address some issues to make the dream come true. Firstly, the exact antiviral mechanism of these carbon dots is still not much explored and most of the literature reported an early stage inhibition except few. Secondly, the in vivo efficacy studies are not much detailed in any of the reported researches and it's difficult to make exact animal models for viral diseases. The mutation capability of the virus is the last but not the least issue. Still, we can expect a bright future for carbon dots in antiviral therapy especially in this urgent situation of COVID-19.

SK: conceptualization, writing—original draft, and funding acquisition. HA and NA: supervision, writing—review, and editing. SB-E, SM, AN, and PD: writing—review and editing. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.