Reversing antibiotic resistance and reprogramming macrophage polarization by extracellular vesicles from fresh...

The rapid global escalation of multi-drug resistant (MDR) infections, ranging from localized chronic MRSA-infected wounds to systemic CRE-induced sepsis, has necessitated the urgent development of innovative antimicrobial potentiators. Herein, we identify Schisandra chinensis-derived extracellular vesicles (SCEVs) as a versatile, biogenic nanoplatform capable of simultaneously reversing bacterial resistance and resolving pathological inflammation. SCEVs exhibit intrinsic, broad-spectrum antibacterial activity and function as potent antibiotic sensitizers. At a low dose, SCEVs reduced the MICs of clinical MDR strains by up to 20-fold, achieving a fractional inhibitory concentration index (FICI) of 0.215. Leveraging this synergy, we engineered meropenem-loaded SCEVs (Mero@SCEVs) to achieve targeted intracellular delivery with an encapsulation efficiency of 20%. Integrated proteomic analyses unveiled that SCEVs exert their multifaceted efficacy through a dual-action mechanism whereby chitinase and Histone H4 disrupt bacterial membrane integrity, while ATP synthase targets F-type ATPase to deplete intracellular energy levels in pathogens. Simultaneously, SCEVs exert profound immunomodulatory effects by scavenging 71.4% of excessive ROS and driving macrophage polarization from a pro-inflammatory M1 phenotype to a pro-healing M2 phenotype. To facilitate clinical translation, a ROS-responsive PBA-HAMA/PVA hydrogel was developed for the sustained delivery of SCEVs to diabetic wounds, accelerating closure within 15 days. Beyond topical therapy, intraperitoneal injection of SCEVs rescued 60% of mice from lethal CRE-induced sepsis by suppressing cytokine storms and alleviating multi-organ damage. Collectively, this work establishes SCEVs as a novel antibiotic adjuvant strategy with dual antimicrobial and immunomodulatory pharmacology for managing the drug-resistant bacterial infectious continuum from localized wounds to systemic sepsis.