Injectable antioxidant hydrogel potentiates mesenchymal stem cell-based therapy for intrauterine adhesion treatment via remodeling inflammatory microenvironment

Intrauterine adhesions (IUAs), a leading cause of uterine infertility, present significant therapeutic challenges, with conventional treatments often yielding unsatisfactory reproductive outcomes. Although mesenchymal stem cell (MSC)-based therapies have demonstrated considerable promise, current biomaterial delivery systems face critical limitations, particularly in addressing the oxidative stress and inflammatory microenvironment of the damaged endometrium that impairs stem cell viability and function. Herein, we developed an injectable antioxidant hydrogel incorporating microspheres loaded with umbilical cord-derived MSCs (TPG hydrogel) for endometrial regeneration and fertility restoration. The TPG hydrogel was formed via dynamic phenylboronic ester crosslinking, endowing it with shear-thinning injectability for minimally invasive administration and potent reactive oxygen species (ROS) scavenging capacity to mitigate oxidative stress. This antioxidant microenvironment protected encapsulated MSCs from oxidative damage, thereby enhancing their therapeutic efficacy. Furthermore, the incorporation of EPLQLKM (E7) peptide-modified gelatin microspheres provided a bioactive niche that promoted cell adhesion and proliferation. Comprehensive in vitro and in vivo studies demonstrated that the TPG hydrogel exhibited dual functionality, including effective ROS scavenging and immunomodulatory effects characterized by the promotion of macrophage polarization toward the anti-inflammatory M2 phenotype. In a rat model of IUAs, the TPG hydrogel significantly enhanced endometrial regeneration and restored fertility. These findings highlight the TPG hydrogel as a promising therapeutic platform for the treatment of endometrial injury and fertility impairment associated with IUAs.