Tagged extracellular vesicles with the RBD of the viral spike protein for delivery of antiviral agents against SARS-COV-2 infection.

The worldwide spread of COVID-19 highlights the urgent need for an efficient approach to rapidly develop therapeutics and prophylactics against SARS-CoV-2. Extracellular vesicle(EVs) are recognized and endocytosed by tissue cells via specific interactions between surface membrane proteins, where after they deliver their molecular cargo. This provides the potential to modify membrane proteins at EV surfaces as a promising means for specific tissue targeting and drug delivery. In this study, we describe a VSVG viral pseudotyping-based approach to load EV membranes with the receptor-binding domain (RBD) of the viral spike protein, the key domain in SARS-CoV-2 attachment, fusion and cellular entry. The RBD-tagged EVs can specifically recognize ACE2 receptor on the surface of target cells, which is required for the RBD-tagged EVs cellular uptake and targeting. Further, using the hACE2 transgenic mouse model, we show the RBD-tagged EVs accumulate specifically in the target tissues that highly express ACE2. Finally, we demonstrate that the RBD-tagged EVs that encapsulate siRNAs against SARS-CoV-2 pseudovirus can specifically target lung tissues and suppress the pseudovirus infection in vivo. Together, our work presents a safe and effective engineered EV system for in vivo targeted delivery of potential antiviral agents into specific tissues which as a therapeutic potential against SARS-CoV-2 infection.