LAUSR

SARS‐CoV‐2 spike (S) protein is crucial for virus invasion in COVID‐19. Here, we showed that lipopolysaccharide (LPS) can trigger S protein aggregation at high doses of LPS and S protein. We demonstrated the formation of S protein aggregates by microscopy analyses, aggregation and gel shift assays. LPS at high levels boosts the formation of S protein aggregates as detected by amytracker and thioflavin T dyes that specifically bind to aggregating proteins. We validated the role of LPS by blocking the formation of aggregates by the endotoxin‐scavenging thrombin‐derived peptide TCP‐25. Aggregation‐prone sequences in S protein are predicted to be nearby LPS binding sites, while molecular simulations showed stable formation of S protein–LPS higher‐order oligomers. Collectively, our results provide evidence of LPS‐induced S protein aggregation.