Biocatalytic Nanoregulators Restore Joint Redox‐Immune Homeostasis in Rheumatoid Arthritis

Abstract Rheumatoid arthritis (RA), a debilitating autoimmune disorder marked by progressive synovitis and osteochondral erosion, presents critical therapeutic challenges due to the limitations of existing regimens, including non‐specific biodistribution and compromised risk‐benefit profiles. In this study, a novel therapeutic approach is proposed utilizing mesenchymal stem cell‐derived extracellular vesicles (EVs) coating on ruthenium‐loaded metal‐organic frameworks (Ru@ZrMOF), which exhibit catalase mimetic activities. The EVs coating enhances the biocompatibility and targeting efficiency of the Ru@ZrMOF, while also promoting cartilage protection. Through reactive oxygen species (ROS) scavenging and oxygen production, Ru@ZrMOF/EVs significantly alleviate joint inflammation, promote cartilage protection, and inhibit pannus formation. The therapeutic mechanism involves polarization of macrophages from the M1 pro‐inflammatory phenotype to the M2 anti‐inflammatory phenotype, facilitating a shift in cytokine profiles from pro‐inflammatory to anti‐inflammatory, and downregulation of hypoxia inducible factor‐1α. These findings demonstrate that Ru@ZrMOF/EVs offer a promising strategy for RA treatment by addressing both inflammation and tissue protection through targeted ROS regulation and immune modulation.