Molecular mechanisms behind the anti corona virus activity of small metal oxide nanoparticles

The recent COVID-19 pandemic has set a strong quest for advanced understanding of possible tracks in abating and eliminating viral infections. In the view that several families of "pristine" small oxide nanoparticles (NPs) have demonstrated viricidal activity against SARS-CoV-2, we studied the effect of two NPs, with presumably different reactivity, on two viruses aiming to evaluate two "primary suspect" routes of their antiviral activity, either specific blocking of surface proteins or causing membrane disruption. The chosen NPs were non-photoactive 3.5 nm triethanolamine terminated (surface capped) titania TiO₂ NPs (TATT) and ultrasmall (1.1 nm) silicotungstate polyoxometalate (POM) NPs. The former were expected to both, interact with viral surface proteins as well as strongly complex with phosphate groups whereas the latter was not expected to form surface complexes. We demonstrated that expectedly, POM NPs up to 1.25 mM (4.5 mg l^-1) had no significant antiviral activity towards neither of the used viruses, an enveloped transmissible gastroenteritis virus (TGEV) belonging to coronaviruses and non-enveloped encelomyocarditis virus (EMCV). At the same time, TATT NPs exhibited statistically significant (p < 0.05) antiviral activity against TGEV starting from 0.125 mM (12 μg ml^-1). However, no antiviral activity of TATT against non-enveloped EMCV was detected. The observation that TATT NPs showed activity only against enveloped viruses and at relatively high concentrations suggests that the effect could be related with complexation with phospholipids. Possible chemical mechanism of viral membrane disruption was investigated by a variable temperature NMR study of NP complexation with model organic phosphate molecules, proving TATT to strongly interact with them and POM remain unreacted. Viral membrane disruption by TATT NPs was additionally confirmed by demonstraing RNA leackage from TGEV upon contact with those NPs. Therefore, our study proved a new mechanism of antiviral action of titania NPs in the dark which involved membrane disruption proceeding via direct surface complexation.