Self‐Assembled Myricetin‐Arginine Conjugate Nanozymes for Targeted Suppression of Joint Inflammation and Osteoclastogenesis in Rheumatoid Arthritis

ABSTRACT Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation and progressive joint destruction driven by macrophage polarization and osteoclast activation. Current therapies lack lesion‐specificity and cause systemic side effects, highlighting the need for targeted treatment strategies. Here, we developed carrier‐free myricetin‐arginine conjugate nanozymes (MANZs) via a Mannich reaction‐mediated conjugation of l ‐arginine and myricetin, followed by self‐assembly driven by noncovalent interaction. The MANZs selectively target M1 macrophages via cationic amino acid transporter 2 (CAT2)‐mediated uptake, facilitating preferential accumulation in inflamed joints. MANZs exert multi‐modal therapeutic effects by scavenging reactive oxygen species (ROS), repolarizing M1 macrophages, and inhibiting osteoclast differentiation. In a collagen‐induced arthritis (CIA) mouse model, MANZs significantly alleviated joint swelling, synovitis, and bone erosion without systemic toxicity. This work establishes a promising paradigm for RA therapy by integrating cationic amino acids with natural polyphenols into a self‐assembled, target‐specific nanoplatform with high biocompatibility and translational potential.