Lipid-coated nanoparticles enhance the delivery of bacterial virulence factors as a potent toxoid vaccine platform against bacterial infections.

Antivirulence vaccination represents a promising strategy for infection prevention, but achieving both safety and efficacy in toxoid vaccine preparation remains a challenge. Cell membrane-based nanotoxoids offer a safe delivery platform for bacterial virulence factors in antivirulence vaccination, but limited absorption capacity hampers their efficacy. Here, we develop a lipid-based toxoid vaccine platform, PSV-CNP, comprising a CpG-loaded polymeric core coated with phosphatidylcholine/sphingomyelin (PS) liposomes enriched with bacterial virulence factors. By enhancing virulence factor absorption, PSV-CNP elicits robust humoral immunity. In mice, it provides long-lasting protection against methicillin-resistant Staphylococcus aureus (MRSA) and clinically isolated S. aureus (CI-SA), even under immunosuppression. In Bama pigs, PSV-CNP induces strong immune responses and prevents MRSA and CI-SA invasion. Furthermore, PS-liposomes efficiently absorb virulence factors from Pseudomonas aeruginosa (PA), conferring protection against PA infections. This study establishes PS-coated nanoparticles as a broadly applicable, safe, and effective antivirulence toxoid vaccine platform.