Clinically Validated Leptin Receptor as a Target for Liposomal Delivery of Metformin in Endometriosis Therapy

Endometriosis is a common, estrogen-driven chronic gynecologic disorder defined by the ectopic growth of endometrial-like tissue within the peritoneal cavity. Existing treatment options, primarily surgery and hormonal therapy, are limited by inconsistent efficacy and treatment-related adverse effects. A major challenge in developing effective therapies is the lack of drug delivery strategies that specifically target ectopic lesions. In this study, we demonstrate through clinical analyses that the Leptin receptor (LEPR) is strongly associated with endometriosis and that its expression is independent of age, menstrual cycle phase, pelvic pain, infertility history, and disease stage. Leveraging this insight, we designed a liposomal delivery platform (HLipo) modified with the HY7 peptide to target LEPR, enabling highly specific delivery to ectopic lesions in a mouse model. Notably, LEPR blockade or mutation abolished this lesion-specific accumulation, further supporting the LEPR-dependent targeting of HLipo. Building on this platform, we developed Met@HLipo, a metformin-loaded formulation that exhibited markedly superior antiendometriotic efficacy compared with free metformin, without detectable toxicity. Mechanistically, our study identifies a therapeutic mechanism whereby Met@HLipo induces autophagy-mediated degradation of Estrogen receptor β (ERβ), thereby directly targeting a central driver of endometriosis pathogenesis. These findings highlight a clinically validated molecular target and present a highly translational, nonhormonal, and nonsurgical therapeutic strategy for endometriosis.