Neutrophil-mediated delivery of hybrid cross-species nanovesicles for treatment of bacterial infections

Hybrid vesicles are increasingly employed as nanocarrier systems for drug delivery owing to their versatile functionalities. This study presents a multifunctional vesicle delivery platform, designated PMB@LNV-SyBV, which integrates anti-inflammatory lemon-derived exosomes and attenuated bacterial vesicles to deliver polymyxin B (PMB). The incorporation of exogenous cholesterol enhances the drug-loading capacity of these vesicles. Antimicrobial assays confirm that PMB@LNV-SyBV effectively targets carbapenem-resistant Gram-negative bacteria. By inheriting pathogen-associated molecular patterns from native bacteria, PMB@LNV-SyBV is efficiently recognized and internalized by neutrophils, enabling it to reach infection sites alongside neutrophil recruitment. Subsequently, the vesicles are released from neutrophils in response to inflammatory stimuli. In infection models involving Klebsiella pneumoniae-induced mouse pneumonia and K. pneumoniae/Escherichia coli-induced mouse bloodstream infections, PMB@LNV-SyBV significantly reduces bacterial load, modulates pro-inflammatory cytokine release, and increases sepsis survival rates. With its high yield and favorable biocompatibility, the multifunctional PMB@LNV-SyBV represents a promising therapeutic platform for the clinical management of carbapenem-resistant bacterial infections.