Preactivated macrophage membrane vesicle-engineered yolk-shell nanoplatform for dual-targeted mild photothermal-triggered cascade gas therapy in MRSA-infected bone and soft tissue regeneration.

MRSA associated infections in skeletal and soft tissues remain formidable clinical issues with limited treatments, due to antibiotic resistance, biofilm formation and pathological hypoxia. Herein, yolk-shell nanoplatform (BMP@M) is developed for targeted mild photothermal-triggered cascade gas therapy against MRSA infections. BMP@M features a polydopamine photothermal yolk and mesoporous MnO2 shell loaded with NO donor (BNN6), enabling spatially separated heat generation and cascade NO release via gradual photothermal conduction. Macrophages are preactivated with MRSA membrane vesicles (MVs) to obtain engineered macrophage MVs with elevated Toll-like receptor 2, endowing BMP@M with MRSA-specific targeting and infectious lesion-targeting ability. The photothermal effect of BMP@M further promotes injectable thermosensitive chitosan to form tissue repair matrix (BMP@M/C). The synergistic photothermal-gas therapy effectively eradicates MRSA and disrupts biofilms. Moreover, the MnO2 shell in situ decomposes pathological H2O2 into O2, alleviating hypoxia. The coordinated release of NO and O2 restores mitochondrial function, scavenges ROS, suppresses NF-κB/NLRP3 inflammatory axis, and drives M2 polarization. In models of MRSA-induced osteomyelitis and full-thickness skin defects, BMP@M/C achieves effective infection control, anti-inflammatory, osteogenesis and angiogenesis effects. This study offers a combined antibacterial, immunomodulatory, and regenerative approach for infected tissue repair.