An Injectable ROS‐Responsive Nanozyme Hydrogel Regulates the Uterine Microenvironment to Prevent Intrauterine Adhesions

Abstract

ABSTRACT Intrauterine injury triggers a self‐reinforcing cycle of inflammation, oxidative stress, and fibrosis that culminates in intrauterine adhesions (IUA), severely impairing women's reproductive health. Current treatments, including hysteroscopic adhesiolysis combined with hormonal therapy or physical barriers, show high recurrence and cannot simultaneously target these interconnected pathways. Here, we developed an injectable ROS‐responsive hydrogel (GPP) loaded with cerium–tannic acid metal‐phenolic nanozymes (CeTA) that exhibit superoxide dismutase (SOD)‐ and catalase (CAT)‐mimetic activities. Unlike passive barriers, its boronate ester‐crosslinked network remains stable under physiological conditions but is selectively cleaved in ROS‐rich inflammatory microenvironments, enabling on‐demand, lesion‐localized CeTA delivery. In vitro, by scavenging excess superoxide and hydrogen peroxide, CeTA alleviated oxidative stress, restored mitochondrial membrane potential, promoted macrophage repolarization from the pro‐inflammatory M1 to the anti‐inflammatory M2 phenotype, and reversed TGF‐β1‐induced fibrosis in endometrial stromal cells. In a rat IUA model, CeTA@GPP hydrogel restored uterine antioxidant enzyme activity, suppressed TGF‐β1 expression and myofibroblast activation, and enhanced cell proliferation and angiogenesis; transcriptomic profiling confirmed coordinated down‐regulation of the inflammation, oxidative stress, and fibrosis pathways. Accordingly, CeTA@GPP hydrogel promoted structural and functional endometrial regeneration and improved endometrial receptivity. By integrating minimally invasive injectability, physical barrier protection, and intelligent ROS‐responsive multi‐target bioactivity, CeTA@GPP hydrogel provides a promising strategy for IUA.