Conversion of Host Cell Receptor into Virus Destructor by Immunodisc to Neutralize Diverse SARS‐CoV‐2 Variants

Abstract The decreasing efficacy of antiviral drugs due to viral mutations highlights the challenge of developing a single agent targeting multiple strains. Using host cell viral receptors as competitive inhibitors is promising, but their low potency and membrane‐bound nature have limited this strategy. In this study, the authors show that angiotensin‐converting enzyme 2 (ACE2) in a planar membrane patch can effectively neutralize all tested severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants that emerged during the COVID‐19 pandemic. The ACE2‐incorporated membrane patch implemented using nanodiscs replicated the spike‐mediated membrane fusion process outside the host cell, resulting in virus lysis, extracellular RNA release, and potent antiviral activity. While neutralizing antibodies became ineffective as the SARS‐CoV‐2 evolved to better penetrate host cells the ACE2‐incorporated nanodiscs became more potent, highlighting the advantages of using receptor‐incorporated nanodiscs for antiviral purposes. ACE2‐incorporated immunodisc, an Fc fusion nanodisc developed in this study, completely protected humanized mice infected with SARS‐CoV‐2 after prolonged retention in the airways. This study demonstrates that the incorporation of viral receptors into immunodisc transforms the entry gate into a potent virucide for all current and future variants, a concept that can be extended to different viruses.