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.