Vancomycin-Loaded Isogenous Membrane Vesicles for Macrophage Activation and Intracellular Methicillin-Resistant Elimination.

Introduction: Methicillin-resistant (MRSA), a notorious multidrug-resistant (MDR) pathogen, frequently resides and proliferates within macrophages, contributing to refractory and recurrent infections. Conventional antibiotics exhibit limited efficacy against intracellular MRSA due to poor cellular penetration.

Methods: Vancomycin (VAN) was encapsulated into membrane vesicles (MVs) derived from the attenuated strain RN4220Δ, generating VAN-loaded nanoparticles (MV-VAN). In vitro and in vivo experiments were performed to test the efficacy of MV-VAN in intracellular MRSA clearance.

Results: MV-VAN demonstrated sustained VAN release and efficient extracellular MRSA eradication. Moreover, macrophages actively internalized MV-VAN, leading to VAN accumulation in intracellular compartments and M1 macrophage polarization, which increased MRSA killing. In vivo animal experiments revealed that MV-VAN was safe and effectively eliminated intracellular MRSA in abdominal infections.

Conclusion: Our findings propose a nanotherapeutic strategy that uses bacterial-derived vesicles for targeted antibiotic delivery, overcoming the intrinsic limitations of conventional therapies against intracellular MDR pathogens.