Cell membrane camouflaged and ROS responsive nanosomes for targeted endometriosis therapy via reversing inflammatory, low-autophagy, and immunotolerant microenvironment

Endometriosis (EMS) is an estrogen-dependent inflammatory disorder defined as the aberrant growth of endometrial tissue outside the uterine cavity. Unfortunately, there is no cure for EMS treatment in current clinical practices. Herein, a neutrophil membrane-cloaked, natural anti-EMS agent leonurine (Leo)-loaded and ROS-responsive nanoplatform (Leo@NM-rLipo) was constructed to remodel the complex lesion microenvironment for efficient EMS alleviation. Owing to the inflammation tropism inherited from neutrophils, Leo@NM-rLipo can target and accumulate in ectopic lesions where high-level ROS can accelerate drug release. Comprehensive studies demonstrated that Leo@NM-rLipo acted as neutrophil nanodecoys to effectively diminish neutrophil infiltration and attenuate proinflammatory cyto/chemokine production. Besides, Leo@NM-rLipo promoted the autophagy-induced apoptosis of ectopic endometrial stromal cells (eESC) by regulating estrogen-ERα signaling and progesterone receptor isoform B (PRB) expression. Furthermore, Leo@NM-rLipo inhibited the expansion and immunosuppressive cytokine production of Tregs to normalize the immune surveillance in the peritoneal cavity. Consequently, Leo@NM-rLipo successfully alleviated EMS as corroborated by tremendously reduced lesion number and weights, attenuated fibrosis, and inhibited collageneogensis in the mice ectopic focus. Furthermore, Leo@NM-rLipo demonstrated excellent biocompatibility both in vitro and in vivo. Taken together, our study for the first time provided a cell-mimetic nanoplatform for targeted EMS therapy, which represents a promising strategy for the treatment of a variety of refractory inflammatory diseases.