A hollow MnO2 nanozymes empowered injectable hydrogel for intrauterine adhesion therapy by alleviating oxidative stress and promoting endometrial repair

Abstract

Intrauterine adhesion (IUA) is an important cause of infertility and poses a challenge to women's reproductive health. However, conventional clinical treatments fail to fundamentally repair the function of the endometrium. While stem cell therapy is a promising breakthrough in IUA treatment, its clinical application remains limited. Recent studies have highlighted the pivotal roles of oxidative stress and inflammatory immune responses in IUA pathogenesis, underlining the requirement for excessive reactive oxygen species (ROS)-scavenging ability, where nanozymes demonstrated distinctive advantages. Herein, we report the preparation of a nanozyme-powered injectable hydrogel (HME) by integrating hollow estradiol-loaded MnO₂ nanoparticles (MnO₂@E2 NPs) with a hyaluronic acid-based hydrogel to explore its therapeutic effect in IUA. In vitro studies demonstrated that MnO₂@E2 NPs exhibited catalase (CAT)-like and superoxide dismutase (SOD)-like enzymatic activities, effectively scavenging ROS. The HME possessed optimal mechanical properties, biocompatibility, robust antioxidant activities and regulatory properties on macrophages, thereby protecting human endometrial stromal cells (HESCs) and enhancing their proliferation. In a rat endometrial injury model, HME treatment regulated the uterine inflammatory microenvironment, suppressed M1 macrophage expression and further promoted endometrial repair. In conclusion, the HME offers a novel and effective therapeutic approach for IUA, with potential clinical implications for women of reproductive age.