Extracellular Vesicle-Mimetic Nanoplatforms for Integrated Vaccination and Targeted Antibiotic Therapy against MRSA Bacteremia: A Wolf in Sheep's Clothing

Methicillin-resistant Staphylococcus aureus (MRSA) remains a critical global health threat, necessitating innovative therapeutic strategies. Inspired by the multi-antigenic features and homotypic binding of MRSA extracellular vesicles (EVs), we aimed to develop a biomimetic nanoplatform cloaked with MRSA-derived EV, termed EV-NP, to integrate vaccine and antibiotic functionalities. EV-NP were efficiently internalized by macrophages and dendritic cells, promoting robust humoral and cellular immune responses, as evidenced by elevated immunoglobulin G titers and CD69 expression. When loaded with rifampicin (RF), the nanoplatform demonstrated homologous targeting to MRSA via EV-mediated adhesion, enhancing drug delivery to intracellular bacteria and biofilm. In a murine bacteremia model, EV-NP vaccination and RF-loaded EV-NP therapy each significantly reduced bacterial burden and proinflammatory cytokine expression, improving survival to 62 and 41 h, respectively. Sequential prophylaxis and therapy extended survival to 140 h. The EV-NP system also attenuated EV-associated hemolysis and showed no acute toxicity. This "wolf-in-sheep's-clothing" strategy offers a versatile approach for both prevention and treatment of MRSA infection.