Short fibers recruiting inflammatory exudate via smart-responsive estrogen antagonism for endometrial hyperplasia

Inflammation-mediated progesterone resistance, driven by the sustained acidification of the inflammatory microenvironment from V-type H⁺-ATPase overexpression in inflammatory cells, critically impedes the treatment of endometrial hyperplasia (EH). Herein, a smart short-fiber scaffold (PGCL) was innovatively fabricated by covalently conjugating levonorgestrel (LNG) to poly (lactic acid)/gelatin nanofibers via a two-step click chemistry approach. The fibers recruit inflammatory fluid and respond intelligently to the acidic inflammatory microenvironment through triazole bond cleavage, enabling targeted LNG release for estrogen antagonism and microenvironment regulation. Specifically, within the mildly acidic lesion site, hydrogen ions trigger the rupture of triazole bonds, resulting in the controlled release of LNG to precisely treat EH. Meanwhile, the highly absorbent and self-expanding properties of PGCL enable adaptation to the complex uterine architecture, while its porous structure (>85% porosity) facilitates inflammatory exudate recruitment. Transcriptomic analysis revealed that PGCL alleviates progesterone resistance by inhibiting the PI3K/AKT/NF-κB pathway, which modulates macrophage polarization and reduces V-type H⁺-ATPase expression, thereby suppressing proliferation through DNA synthesis blockade and downregulating VEGF and pro-inflammatory factors. In EH model rats, PGCL treatment reduced endometrial thickness by 32.45%, gland density by 41.24%, and inflammatory factor expression by 38.22-55.58% in EH model rats. Short fibers that recruit inflammatory exudate enable a novel strategy for endometrial repair through smart-responsive estrogen antagonism.