Biocatalytic and Redox‐Regulated Nanoarchitectures for Precision Inflammation and Immune Homeostasis Modulation to Combat Rheumatoid Arthritis

Abstract The chronic inflammatory milieu of rheumatoid arthritis (RA), marked by elevated reactive oxygen species (ROS), perpetually activated pro‐inflammatory macrophages (M1) and osteoclasts, and significant infiltration of pro‐inflammatory cytokines contributes to abnormal articular redox imbalance, severe synovitis, and progressive joint erosion. In this study, the rational design of a biocatalytic and redox‐regulated nanoarchitecture comprising Ru cluster‐anchored hydroxylated Fe₂O₃ (Ru‐HFO) encapsulated within bone marrow stem cell‐derived extracellular vesicles (BEVs), for precision inflammation modulation to combat RA is proposed. When combined with ultrasound (US) stimulation, this biocatalytic and inflammation‐targeting nanoarchitecture (BEVs@Ru‐HFO) can reprogram macrophages and osteoclasts to restore redox and immune homeostasis, thereby alleviating RA. The findings reveal that the hydroxylation strategy enhances electron density at Ru redox centers and fine‐tunes the binding affinity of oxygen intermediates, thereby ensuring exceptional multi‐enzymatic ROS‐scavenging activities. Notably, under ultrasonic irradiation, BEVs@Ru‐HFO targets inflamed joints, promotes the local accumulation of anti‐inflammatory macrophages, downregulates inflammatory cytokines, and ameliorates the hypoxic microenvironment to inhibit osteoclastogenesis. This ultimately confers bone and cartilage protection and restores joint function. It is posit that this biocatalytic and redox‐regulated nanoarchitecture, with its superior antioxidant and immunomodulatory capabilities, represents a promising strategy for engineering ROS‐catalytic materials to treat RA and potentially many other autoimmune diseases.