Exosomal lncRNA OTUD6B-AS1 as a pathogenic nanocarrier promotes inflammatory macrophage polarization in endometritis via a targetable ceRNA circuit

Endometritis, a major inflammatory cause of infertility, is driven by unresolved immune dysregulation in which macrophage polarization is critical. Yet, how inflammatory signaling is spatially propagated within the endometrial microenvironment remains unclear. Here, we report that exosomes—natural nanoscale extracellular vesicles—released from lipopolysaccharide (LPS)-injured endometrial epithelial cells (EECs) act as pathogenic nanocarriers that fuel macrophage-dependent inflammation. We demonstrate that LPS enhances exosome biogenesis and secretion via the AKT/ATG16L1 pathway. These exosomes efficiently deliver their molecular cargo to macrophages, triggering NF-κB activation and polarizing them toward a pro-inflammatory M1 phenotype. RNA sequencing identified lncRNA OTUD6B-AS1 as a highly enriched cargo in exosomes from inflamed EECs. Functional studies established that exosome-mediated transfer of lncRNA OTUD6B-AS1 is both necessary and sufficient to drive M1 polarization. Mechanistically, lncRNA OTUD6B-AS1 functions as a competing endogenous RNA (ceRNA), sequestering miR-128 to relieve its repression on Notch2, thereby amplifying NF-κB signaling. This axis was validated in clinical endometritis tissues, which exhibited elevated lncRNA OTUD6B-AS1 and Notch2 alongside reduced miR-128. Importantly, targeting this pathway—through genetic knockdown of lncRNA OTUD6B-AS1 or pharmacological inhibition of the miR-128/Notch2 node—abolished the pro-inflammatory effects. Our work not only delineates a new exosome-coordinated signaling circuit in endometritis but also highlights exosomes as druggable natural nanoparticles. These findings position exosome-based engineering—such as cargo modulation or designed vesicle delivery—as a promising nanomedicine strategy to intercept pathological cell-cell communication and treat inflammatory diseases.