A decoy virus strategy using plant-produced SARS-CoV-2 virus-like-particles to inhibit infection and lung injury

The rapid emergence of highly transmissible and immune-evasive SARS-CoV-2 variants, including Omicron lineage strains, has reduced the effectiveness of existing vaccines and antiviral therapies. Safe and rapidly deployable biologics capable of limiting viral entry and attenuating early inflammatory responses remains needed, particularly for high-risk exposure settings. We evaluated engineered non-replicating SARS-CoV-2 virus-like particles (VLPs), which structurally mimic the native virus, for antiviral and immunomodulatory effects in human induced pluripotent stem cell (iPSC)–derived lung organoids and K18-hACE2 transgenic mice. Cytopathic effects, viral RNA levels, cytokine expression, and lung pathology were quantified, while biodistribution and acute safety were assessed by fluorescence imaging and inflammatory profiling. Pre-exposure of lung organoids to VLPs attenuated SARS-CoV-2–induced cytopathic injury, reduced viral replication and IL-6 expression, and preserved epithelial integrity. Intranasal administration in K18-human angiotensin-converting enzyme 2 (ACE2) mice achieved uniform pulmonary distribution without acute inflammatory responses. A single pre-exposure prophylaxis dose of high-titer VLPs reduced viral burden and IL-6 levels, attenuated lung injury, and improved clinical parameters. Fluorescent VLPs co-localized with ACE2 and underwent cellular uptake in Calu-3 cells, supporting a competitive decoy mechanism, while preservation of ACE2 expression in vivo suggested reduced virus-induced ACE2 downregulation. SARS-CoV-2 VLPs function as safe, non-replicating biologics that limit viral entry and attenuate downstream inflammation under pre-exposure conditions. Their stability, scalability, and intranasal support further development as a pre-exposure prophylactic strategy, while additional studies are required to determine efficacy against contemporary variants and under post-exposure conditions. Plant-derived SARS-CoV-2 VLPs function as decoys to block viral entry and protect the lung. SARS-CoV-2 VLPs acts as safe, non-replicating biologics that competitively block viral entry via ACE2, attenuated inflammation, and provide a rapidly translatable intranasal strategy for prophylaxis and therapy against current and emerging variants. Figure created with BioRender (https://BioRender.com/2ba9w98).