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

Methicillin-resistant Staphylococcus aureus (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.

Vancomycin (VAN) was encapsulated into membrane vesicles (^ΔagrAMVs) derived from the attenuated S. aureus strain RN4220ΔagrA, generating VAN-loaded nanoparticles (^ΔagrAMV-VAN). In vitro and in vivo experiments were performed to test the efficacy of ^ΔagrAMV-VAN in intracellular MRSA clearance.

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

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.