Recent Advances in Non-Hormonal Drug Delivery Strategies for Endometriosis Management

Endometriosis is a chronic, estrogen-dependent inflammatory disorder affecting ~10% of reproductive-aged women, yet current hormonal therapies offer only symptom management, cause significant side effects, and preclude fertility. This comprehensive review synthesizes evidence from 47 studies (2023–2026) on emerging non hormonal nanomedicine strategies that target disease mechanisms independent of estrogen—including angiogenesis (VEGF/HIF 1α), inflammation (COX 2, TNF α, interleukins), matrix metalloproteinases (MMP 2/ 9), oxidative stress/iron overload (ROS, heme), and estrogen independent proliferative pathways (PI3K/Akt/mTOR). Advanced particulate delivery systems—PEGylated liposomes, PLGA and chitosan nanoparticles, ROS responsive nanocarriers, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs)—have demonstrated marked preclinical efficacy. Active targeting using folate, LHRH, integrin (RGD), or Frizzled 7 ligands improves lesion accumulation 3 to 12 fold, achieving lesion volume reductions of 59–82% while preserving ovarian function and fertility. Local and site specific systems (thermosensitive hydrogels, pH responsive gels, microneedle patches, intraperitoneal depots, and the Hyivy intravaginal device) enable sustained release with single administration; the Hyivy device reduced VAS pain scores from 7.2 to 2.5 at six months in a Phase II trial. Emerging bioinspired platforms—MSC derived exosomes, macrophage hitchhiking carriers, MMP cleavable peptide conjugates, and photothermal liposomes—have achieved lesion reductions up to 92%. Despite these advances, translational gaps remain: only 5/47 studies reported GMP compatible manufacturing, long term safety data beyond six months are scarce, and efficacy by endometriosis subtype is unexplored. However, with one FR targeted liposomal artesunate formulation qualified under the FDA ISTAND program and four ongoing clinical trials, non hormonal nanomedicines represent a paradigm shift toward fertility sparing, mechanism targeted therapies for endometriosis and related benign gynecologic disorders.