Neutrophil hitchhiking liposomal drugs for starvation therapy in endometriosis

Rationale: Endometriosis, characterized by the presence of ectopic endometrial-like tissue, is a common chronic inflammatory disorder in gynecology. However, current treatments, including surgery and hormone therapy, often yield suboptimal outcomes and significant adverse effects. The lack of a drug delivery system specifically targeting ectopic lesions remains a major barrier to the development of more effective treatments. Methods: To exploit the continuous recruitment of neutrophils and elevated reactive oxygen species (ROS) levels within endometriotic lesions, we designed a ROS-responsive liposome (cLipo) modified with neutrophil-targeting peptides on its surface. A minimally invasive mouse model of endometriosis was used to assess the neutrophil-mediated delivery of cLipo. Additionally, we co-loaded the glucose analog 2-deoxy-D-glucose (2-DG) and the autophagy inhibitor chloroquine (CQ) into the liposomes, resulting in the formulation termed cLipo-DC. The therapeutic efficacy of cLipo-DC was evaluated using human endometriotic cells (12Z), endometrial cancer cells (Ishikawa), and an endometriosis mouse model. Results: Although neutrophil hitchhiking strategies are rarely reported in chronic inflammatory diseases, we found that cLipo specifically bound to neutrophils and accumulated in ectopic lesions following intraperitoneal injection in the endometriosis mouse model. Subsequently, in vitro experiments showed that cLipo-DC effectively inhibited glycolysis and autophagy in both 12Z and Ishikawa cells, resulting in cell death. Furthermore, in vivo administration of cLipo-DC in the endometriosis mouse model exerted a significant anti-endometriosis effect, with no detectable side effects. Conclusions: This study provides a novel neutrophil hitchhiking platform for non-hormonal treatment of endometriosis.