Bone-targeted carbon dots nanogels achieve precision antioxidant therapy for rheumatoid arthritis by activating the endogenous antioxidant system

Carbon dots (CDs) exhibit significant potential as nanozymes for the treatment of rheumatoid arthritis (RA) due to their multi-enzyme mimetic activity. However, their non-specific biodistribution may lead to systemic redox imbalance. Herein, a bone-targeted CD nanogel (n(CD)) was constructed by <i>in situ</i> free radical polymerization of 2-methacryloyloxyethyl phosphorylcholine, forming a three-dimensional porous network that encapsulates multi-enzyme active CDs. The porous polymer shell allows the free diffusion of reactive oxygen species (ROS) and efficiently scavenges them through cascade catalytic reactions. The phosphate groups on the surface of the n(CDs) specifically coordinate with hydroxyapatite in bone tissue, providing precise bone-targeting ability. In collagen-induced arthritis rats, n(CDs) demonstrated prolonged joint retention and effectively suppressed synovial oxidative damage through localized ROS neutralization, while downregulating the expression of pro-inflammatory cytokines and significantly outperforming free CDs. Mechanistic studies revealed that n(CDs) can activate the endogenous antioxidant defense system <i>via</i> upregulation of the heme oxygenase-1 pathway. This study provides a paradigm reference for designing high-specificity nanozyme platforms to treat oxidative stress-related bone and joint diseases through a targeted delivery-<i>in situ</i> catalysis-endogenous activation triple synergy strategy.