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

Abstract

Introduction: 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.

Methods: 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.

Results: ^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.

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.