LAUSR

Significance The recently emerged SARS-CoV-2 variants are more transmissible, which brings new challenges to vaccine treatment. There is an urgent global need for alternative strategies that could effectively and rapidly prevent the infection of various SARS-CoV-2 variants. Herein, we design human angiotensin-converting enzyme II (hACE2)–containing nanocatchers (NCs) derived from genetically engineered cells stably expressing hACE2 as the competitor with host cells for virus binding to protect cells from SARS-CoV-2 infection. An inhalable formulation fabricated by NCs and the mucoadhesive excipient hyaluronic acid could significantly prolong the retention of NCs in the lung and exhibits potent pseudovirus inhibition ability in an hACE2-expressing mouse model. Importantly, the inhalable NCs in the lyophilized formulation allow long-term storage, facilitating their future clinical use. The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome (SARS)–like coronavirus (SARS-CoV-2), presents an urgent health crisis. More recently, an increasing number of mutated strains of SARS-CoV-2 have been identified globally. Such mutations, especially those on the spike glycoprotein to render its higher binding affinity to human angiotensin-converting enzyme II (hACE2) receptors, not only resulted in higher transmission of SARS-CoV-2 but also raised serious concerns regarding the efficacies of vaccines against mutated viruses. Since ACE2 is the virus-binding protein on human cells regardless of viral mutations, we design hACE2-containing nanocatchers (NCs) as the competitor with host cells for virus binding to protect cells from SARS-CoV-2 infection. The hACE2-containing NCs, derived from the cellular membrane of genetically engineered cells stably expressing hACE2, exhibited excellent neutralization ability against pseudoviruses of both wild-type SARS-CoV-2 and the D614G variant. To prevent SARS-CoV-2 infections in the lung, the most vulnerable organ for COVID-19, we develop an inhalable formulation by mixing hACE2-containing NCs with mucoadhesive excipient hyaluronic acid, the latter of which could significantly prolong the retention of NCs in the lung after inhalation. Excitingly, inhalation of our formulation could lead to potent pseudovirus inhibition ability in hACE2-expressing mouse model, without imposing any appreciable side effects. Importantly, our inhalable hACE2-containing NCs in the lyophilized formulation would allow long-term storage, facilitating their future clinical use. Thus, this work may provide an alternative tactic to inhibit SARS-CoV-2 infections even with different mutations, exhibiting great potential for treatment of the ongoing COVID-19 epidemic.