Puerarin-Loaded Peptide Hydrogel Restores Endometrial Function and Fertility in Intrauterine Adhesion.

Intrauterine adhesion (IUA) is a leading cause of female infertility with suboptimal clinical treatment outcomes. Puerarin (PUE) exhibits potent anti-fibrotic activity. Herein, we fabricated a PUE-loaded peptide hydrogel (PUE-Gel) and investigated its physicochemical properties, biocompatibility, and therapeutic efficacy against IUA, as well as the underlying mechanism. PUE-Gel exhibited excellent biocompatibility, injectability, sustained drug release, and biodegradability. In an in vivo IUA model, PUE-Gel significantly restored injured endometrial morphology, increased gland and blood vessel numbers, and attenuated fibrosis in IUA rats. It also restored the expression of estrogen/progesterone receptors and integrin ανβ3 to improve endometrial receptivity, along with a markedly enhanced pregnancy rate. Transcriptomic and mechanistic studies suggested that the injury-activated Wnt/β-catenin signaling pathway may contribute to endometrial fibrosis. Collectively, PUE-Gel acts as both a physical anti-adhesion barrier and a localized sustained drug delivery system, effectively alleviating IUA potentially through modulation of the Wnt/β-catenin pathway to promote endometrial regeneration, angiogenesis, and fertility recovery. This work provides a bioactive hydrogel biomaterial and a promising potential strategy for IUA and endometrial damage-induced infertility.