A hollow MnO 2 nanozymes empowered injectable hydrogel for intrauterine adhesions therapy by alleviating oxidative stress and promoting endometrial repair

Abstract

Intrauterine adhesion (IUA) is an important cause of infertility and posese a challenge to women's reproductive health. Conventional clinical treatments fail to fundamentally repair the function of the endometrium. While stem cell therapy represents a promising breakthrough in IUA treatment, its clinical application remains limited. Recent studies highlighted the pivotal roles of oxidative stress and inflammatory immune response in IUA pathogenesis, underlining the requirement of excessive reactive oxygen species (ROS)-scavenging ability where nanozymes demonstrated distinctive advantages. Herein, we reported a nanozyme-empowered injectable hydrogel (HME) by integrating hollow estradiol-loaded MnO2 nanoparticles (MnO2@E2 NPs) with 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. HME hydrogel possessed optimal mechanical properties, biocompatibility, robust antioxidant activities and regulatory properties of 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 the endometrial repair. In conclusion, HME hydrogel offers a novel and effective therapeutic approach for IUA, with potential clinical implications for women of reproductive age.