Abstract
The binding of viruses to host-entry factor receptors is an essential step for viral infection. Many studies have shown that macrophages can internalize viruses and degrade them in lysosomes for clearance in vivo. Inspired by these natural behaviors and using SARS-CoV-2 as a testbed, we harvest lysosomes from activated macrophages and anchor the protein-receptor ACE2 as bait, thus constructing a lysosomal "TRAP" (lysoTRAP) that selectively captures, internalizes, and eventually degrades SARS-CoV-2. Through experiments with cells, female mice, female hamsters, and human lung organoids, we demonstrate that lysoTRAP effectively clears SARS-CoV-2. Importantly, unlike therapeutic agents targeting SARS-CoV-2 spike protein, lysoTRAP remains effective against nine pseudotyped variants and the authentic Omicron variant, demonstrating its resistance to SARS-CoV-2 mutations. In addition to the protein-receptor ACE2, we also extend lysoTRAP with the saccharide-receptor sialic acid and verify its excellent antiviral effect against H1N1, highlighting the flexibility of our "TRAP" platform in fighting against various viruses.