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bioRxiv · 10.1101/2025.09.23.677998

Redirection of SARS-CoV-2 to phagocytes by intranasal sACE2-Fc as a universal decoy confers complete prophylactic protection

Wang, J.·Li, J.·Chin, A. W.·Luo, B.·Wei, J.·Qiu, J.·Ren, J.·Xia, Y.·Braun, T.·L M Poon, L. L. M.·Feng, B.
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Abstract

The rapid evolution of SARS-CoV-2 and other respiratory RNA viruses limits the success of current vaccines and antibody-based therapies. Engineered decoy receptors based on soluble angiotensin-converting enzyme 2 (sACE2) offer promising alternatives. Clinical-grade recombinant sACE2 inhibits SARS-CoV-2 replication in vitro but shows limited clinical success. This study reports an optimized sACE2 mutant fused to human IgG1 Fc (B5-D3), which redirects virus-decoy complexes to lysosomal degradation in macrophages. Intranasal prophylactic delivery of B5-D3 confers complete protection in SARS-CoV-2-infected K18-hACE2 mice. Abrogation of Fc effector functions compromises antiviral protection, indicating that Fc-mediated uptake of virus-decoy complexes is critical. Transcriptomic analysis suggests that B5-D3 induces early immune activation in lungs of infected mice. Bio-distribution and flow cytometry reveal selective targeting of airway phagocytes. In vitro assays confirm lysosomal degradation of virus-decoy complexes by macrophages without productive infection. These findings reveal a distinct antiviral mechanism via phagocytic clearance, supporting refined regimens for decoy treatments against SARS-CoV-2 and potentially other respiratory viruses.

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Wang, J., Li, J., Chin, A. W., Luo, B., Wei, J., Qiu, J., Ren, J., Xia, Y., Braun, T., L M Poon, L. L. M., Feng, B.. 2025-09-23. Redirection of SARS-CoV-2 to phagocytes by intranasal sACE2-Fc as a universal decoy confers complete prophylactic protection. https://doi.org/10.1101/2025.09.23.677998

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