ABSTRACT: Intrauterine injury can induce a self-reinforcing vicious cycle involving inflammation, oxidative stress, and fibrosis, ultimately leading to intrauterine adhesions (IUA), which severely impair women’s reproductive health. Current treatments, such as hysteroscopic adhesiolysis combined with hormonal therapy or physical barriers, still show high recurrence rates and are unable to simultaneously regulate the interconnected pathological processes of inflammation, oxidative stress, and fibrosis. In this study, we developed an injectable ROS-responsive hydrogel (CeTA@GPP) loaded with cerium–tannic acid nanoenzymes (CeTA). Unlike passive physical barriers, this hydrogel system remains stable under physiological conditions but can be selectively cleaved in ROS-enriched inflammatory microenvironments, thereby enabling on-demand, lesion-localized CeTA delivery. This system exhibits superoxide dismutase (SOD)- and catalase (CAT)-mimetic activities, allowing it to scavenge excessive ROS, alleviate oxidative stress, restore mitochondrial membrane potential, promote macrophage polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype, and reverse TGF-β1-induced fibrosis in endometrial stromal cells. In a rat model of IUA, CeTA@GPP hydrogel restored uterine antioxidant enzyme activity, promoted macrophage polarization toward the anti-inflammatory M2 phenotype, suppressed TGF-β1 expression and myofibroblast activation, and enhanced cell proliferation and angiogenesis. Transcriptomic analysis further showed that CeTA@GPP hydrogel coordinately downregulated inflammation, oxidative stress, and fibrosis related signaling pathways. Ultimately, CeTA@GPP hydrogel promoted structural and functional regeneration of the endometrium and improved endometrial receptivity. By integrating minimally invasive injectability, physical barrier protection, and intelligent ROS-responsive multi-target bioactivity, CeTA@GPP provides a promising strategy for IUA.
