Reprogramming peritoneal macrophages with outer membrane vesicle-coated PLGA nanoparticles for endometriosis prevention.

Endometriosis is a chronic inflammatory disease that primarily affects women of reproductive age. The current hormonal treatments are unsuitable for women who wish to conceive, highlighting the need for non-hormonal therapeutic alternatives. In this study, we engineered outer membrane vesicle (OMV)-coated poly (lactic-co-glycolic acid) (PLGA) nanoparticles (OMV-NPs) as a potential therapy for endometriosis. These OMV-NPs were internalized by macrophages more efficiently than bacterial OMVs and preserved the immunostimulatory properties of OMVs. In vivo administration of OMV-NPs in mice achieved prolonged retention in the peritoneal cavity, with effective uptake by nearly 80 % of the peritoneal macrophages. Notably, treatment with OMV-NPs reprogrammed macrophages toward the M1 phenotype, resulting in a significant decrease in the M2 to M1 ratio within the peritoneal cavity and in endometriotic lesions. This shift from M2 to M1 was associated with reduced TGF-β1 production and suppressed myofibroblast activation, which led to substantial inhibition of endometriosis progression. Furthermore, immunohistochemical imaging of paired eutopic and ectopic endometrial tissues from endometriosis patients revealed a positive correlation between M2-polarized macrophages and fibrosis. This finding suggests that reprogramming macrophages with OMV-NPs could be a promising therapeutic approach for endometriosis.