MXenzyme-reinforced hydrogel enhances stem cell therapy through multidimensional regulation in rheumatoid arthritis management.

Rheumatoid arthritis (RA) is a devastating autoimmune disorder that imposes health and economic burdens on communities worldwide. Although stem cell transplantation has emerged as a promising option for RA management, the osteoimmune microenvironment that characterizes elevated reactive oxygen/nitrogen species (ROS/RNS) and poor oxygen (O2) supply compromise therapeutic efficiency. To address this issue, we present a nanozyme-reinforced hydrogel designed to modulate the immune microenvironment using a 'turning foes into friends' strategy, thereby enhancing the outcomes of stem cell therapy in RA. This hydrogel scavenges excessive ROS/RNS while synergistically generating O2, making it an effective protective vehicle for bone marrow-derived mesenchymal stem cells (BMSCs). Moreover, it successfully induces macrophage polarization from the M1 to the M2 phenotype and facilitates the osteogenic differentiation of BMSCs, even under hostile oxidative conditions. Furthermore, hydrogel-mediated stem cell therapy is demonstrated to attenuate the onset of exacerbated synovial inflammation and promote bone remodeling in a severe rabbit RA model. This study offers a promising avenue for augmented stem cell therapy efficiency in RA management and provides translational significance for stem cell-based therapy even beyond autoimmune disorders.