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

Xu Y, Yunyu Xu, Yi Xu, Fang Y, Youyan Fang, Yue Wang, Wu R, Rong Wu, Mengni Zhou, Zhou M, Pengcheng Lu, Lu P, Ying Wang, Wang Y, He Y, Y U E J I He, Ye He, Jiqian Zhang, Wei Z, Zhaolian Wei, Zhu S, Shasha Zhu
ACS nano · 2026 · vol. 20(18) , pp. 13542–13559 · doi:10.1021/acsnano.5c18417 · PMID:42054534 · W7158465155
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⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-06-08 ⓘ

Researchers identified leptin receptor as a target for liposomal metformin delivery, demonstrating potent anti-endometriotic efficacy by inducing autophagy-mediated degradation of ERβ.

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The paper investigated whether the leptin receptor (LEPR) is clinically associated with endometriosis and used that finding to develop a targeted liposomal drug delivery system for ectopic lesions. Through clinical analyses, it reported that LEPR expression is strongly associated with endometriosis and is independent of age, menstrual cycle phase, pelvic pain, infertility history, and disease stage, with the key limitation being that the excerpt does not specify sample size or patient selection details. Using a mouse endometriosis model, the authors engineered a HY7-peptide-modified liposomal platform (HLipo) that accumulated specifically in ectopic lesions, with lesion-specific accumulation abolished by LEPR blockade or mutation. They further showed that metformin-loaded HLipo (Met@HLipo) had markedly better antiendometriotic efficacy than free metformin and reduced estrogen receptor β via autophagy-mediated degradation without detectable toxicity. This paper is centrally about endometriosis—LEPR-targeted HY7-modified liposomal metformin delivery and its mechanism via autophagy-mediated ERβ degradation.

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Abstract

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.
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Clinically Validated Leptin Receptor as a Target for Liposomal Delivery of Metformin in Endometriosis TherapyClick to copy article linkArticle link copied! - Yunyu XuYunyu XuDepartment of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei 230022, Anhui, ChinaNHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230032, Anhui, ChinaEngineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No. 81 Meishan Road, Hefei 230032, Anhui, ChinaMore by Yunyu Xu - Youyan FangYouyan FangDepartment of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei 230022, Anhui, ChinaNHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230032, Anhui, ChinaEngineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No. 81 Meishan Road, Hefei 230032, Anhui, ChinaMore by Youyan Fang - Yue WangYue WangDepartment of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei 230022, Anhui, ChinaNHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230032, Anhui, ChinaEngineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No. 81 Meishan Road, Hefei 230032, Anhui, ChinaMore by Yue Wang - Rong WuRong WuDepartment of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei 230022, Anhui, ChinaNHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230032, Anhui, ChinaEngineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No. 81 Meishan Road, Hefei 230032, Anhui, ChinaMore by Rong Wu - Mengni ZhouMengni ZhouDepartment of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei 230022, Anhui, ChinaNHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230032, Anhui, ChinaEngineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No. 81 Meishan Road, Hefei 230032, Anhui, ChinaMore by Mengni Zhou - Pengcheng LuPengcheng LuDepartment of Anesthesiology, the First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, Anhui, ChinaMore by Pengcheng Lu - Ying WangYing WangDepartment of Anesthesiology, the First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, Anhui, ChinaMore by Ying Wang - Ye HeYe HeDepartment of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei 230022, Anhui, ChinaNHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230032, Anhui, ChinaEngineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No. 81 Meishan Road, Hefei 230032, Anhui, ChinaMore by Ye He - Jiqian Zhang*Jiqian Zhang*Email: [email protected]Department of Anesthesiology, the First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, Anhui, ChinaMore by Jiqian Zhang - Zhaolian Wei*Zhaolian Wei*Email: [email protected]Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei 230022, Anhui, ChinaNHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230032, Anhui, ChinaEngineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No. 81 Meishan Road, Hefei 230032, Anhui, ChinaMore by Zhaolian Wei - Shasha Zhu*Shasha Zhu*Email: [email protected]Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No.218 Jixi Road, Hefei 230022, Anhui, ChinaNHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230032, Anhui, ChinaEngineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No. 81 Meishan Road, Hefei 230032, Anhui, ChinaMore by Shasha Zhu Abstract 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. Cited By This article has not yet been cited by other publications. Article Views Altmetric Citations Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days. 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Condition tags

endometriosisinfertility

MeSH descriptors

Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems

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References (53)

SciLite annotations

chemicals 5
metformin estrogen peptide metformin metformin
organisms 1
transgenic mice

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