Engineered Nanovesicles for the Precise and Noninvasive Treatment of Deep Osteomyelitis Caused by MRSA Infection with Enhanced Immune Response.

The clinical treatment of hospital-acquired persistent osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA) presents two major challenges: ineffective drug delivery into deep tissues and counteracting the rapid establishment of an immunosuppressive microenvironment. Indeed, MRSA can evade immunosurveillance and undermine both innate and adaptive immune responses. Herein, the engineered nanovesicles, functioning by combining sonodynamic therapy (SDT) with immune modulation, were constructed for the precise and noninvasive removal of MRSA in deep tissue and activation of the antimicrobial immune response using a newly engineered nanovesicle. Macrophage-derived M1 phenotypic microvesicles (M1-MW) internalized vancomycin-cross-linked micelles with the acoustic sensitizer indocyanine green (ICG) (VCG micelles). The vesicles of M1-MW were grafted with PEGylated mannose, allowing for targeted accumulation at the infection site. The VCG micelles were responsive to the highly reducing environment and released ICG to generate ROS after exposure to ultrasounds. This effect was combined with the presence of vancomycin to kill MRSA. In an osteomyelitis infection model, we observed an improved survival rate and reprogramming of macrophages to a pro-inflammatory M1 phenotype. The latter promoted T-cell activation and immune defense against MRSA-camouflaged homologous cell-transferred infections. Thus, our study presents a noninvasive and efficient treatment (VCG@MMW) for deep osteomyelitis with improved bacterial clearance and reduced risk of recurrence with enhanced immune response.