A Mitochondria‐Modulating Nanosystem for Rheumatoid Arthritis Immunotherapy via Inflammatory Cascade Disruption

ABSTRACT Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation within joints, where macrophage‐driven inflammatory cascade caused by mitochondrial dysfunction significantly contributes to the pathogenesis. Through recruitment and activation of neutrophils from circulation, these macrophages promote the release of neutrophil extracellular traps (NETs) and generation of reactive oxygen species (ROS), leading to synovitis exacerbation and tissue damage. To disrupt this closely linked cycle, we present a mitochondria‐modulating nanosystem (NM@APDAase) targeting the inflammatory cascade for RA immunotherapy. The neutrophil membrane‐camouflaged nanomaterials are directed to inflamed joints, where the released AP39 effectively restores mitochondrial function by serving as a mild electron donor and uncoupler. This reprograms macrophages from a pro‐inflammatory to an anti‐inflammatory phenotype, thereby eliminating the primary source of inflammation. Notably, the co‐loaded DNase I and polydopamine scaffold work synergistically to clear pre‐existing NETs and scavenge ROS. In vivo studies demonstrate that NM@APDAase significantly alleviates RA pathology as evidenced by reduced inflammatory responses, mitigated cartilage erosion and reduced bone destruction. Our work highlights the promise of mitochondria‐modulating nanomaterials for treating RA through directed disruption of the inflammatory cascade.