Synthetic RNA-protein decoy granules to prevent SARS-CoV-2 infection

Summary Synthetic receptor decoys offer a promising strategy to block viral entry but are often limited by instability and rapid clearance. Here we introduce AntiCoV decoy particles: phase-separated synthetic RNA-protein nanoparticles that display multivalent human ACE2 and act as robust decoy receptors for SARS-CoV-2. The granules remain structurally stable for at least two weeks at room temperature. Using confocal imaging and FRET, we show that the SARS-CoV-2 receptor-binding domain is absorbed into the granule matrix with nanometer-scale proximity to ACE2. In viral entry assays with Delta and Omicron (BA.1) variants, AntiCoV decoy particles achieve complete inhibition of infection at low micromolar concentrations and outperform soluble ACE2, which also exhibits infection enhancement at low doses. A minimal kinetic model suggests a multistep spike-priming mechanism that reconciles this biphasic response. AntiCoV decoy particles therefore provide a stable, modular, and pan-variant antiviral platform with potential for low-cost, room-temperature-stable prophylaxis.