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

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.