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

Synthetic decoy receptors offer a promising strategy to block viral entry but are often limited by instability and rapid clearance. In this report article, we introduce anti-coronavirus (antiCoV) decoy particles-phase-separated synthetic RNA-protein nanoparticles that display multivalent human angiotensin-converting enzyme-2 (ACE2) and act as robust decoy receptors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The granules remain structurally stable for at least 2 weeks at room temperature and in varied biological settings. Using confocal imaging and Förster resonance energy transfer, 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 strong 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.