Heparin-Conjugated ACE2-Bearing Extracellular Vesicles As Engineered Dual-Decoy for Combating the SARS-CoV-2 Omicron Variant via Pulmonary Delivery

The very highly contagious Omicron variant of SARS-CoV-2, repeated infection, and long COVID symptoms continue to be a health threat with few convenient preventive or therapeutic methods suitable for common use. Spike-glycan interactions play an essential role in SARS-CoV-2 infections, and heparan sulfate acts as a coreceptor for mediating the cell entry of the virus. In response to this challenge, we proposed a dual-decoy strategy using both heparin (an analogue of heparan sulfate) and ACE2 to neutralize SARS-CoV-2. We developed a heparin-conjugated ACE2-bearing extracellular vesicle system (haEVs), serving as nano dual bait, with high efficiency in neutralizing the Omicron variant through interactions with the viral Spike protein. In vitro experiments showed that haEVs bound to the pseudovirus of SARS-CoV-2 and effectively prevented the pseudovirus infection of host cells. In vivo experiments further demonstrated that inhalable haEVs effectively blocked the pseudovirus infection of lung tissue of the Omicron variant with good biosafety. This dual-decoy approach presents a promising avenue for combating SARS-CoV-2, especially the Omicron variant, with the advantage of self-administration for preventive and therapeutic applications.