Cyanidin-derived antioxidant carbon dots rebalance macrophage-chondrocyte crosstalk for osteoarthritis therapy

Osteoarthritis (OA) progression is closely associated with a ROS-amplified inflammatory microenvironment that promotes macrophage dysregulation, synovitis, and chondrocyte matrix catabolism. However, current antioxidant nanomedicines for OA are often constrained by metal-associated safety concerns, limited cartilage accessibility, and insufficient regulation of macrophage-chondrocyte inflammatory crosstalk. Herein, we report cyanidin-derived antioxidant carbon dots (CC-CDs) as a precursor-programmed nanoscale redox-modulating platform for preventing OA progression. Through a facile one-pot hydrothermal strategy, the intrinsic polyphenolic antioxidant motifs of cyanidin are integrated into an ultrasmall carbon framework, yielding CC-CDs with abundant surface functional groups, potent ROS-scavenging capacity, and superoxide dismutase-like activity. In vitro , CC-CDs suppress LPS-induced M1 macrophage activation, promote M2-associated polarization, and preserve matrix homeostasis in IL-1β-stimulated chondrocytes by restoring SOX9, COL2A1, and aggrecan expression while reducing MMP13 levels. In a murine OA model, intra-articular administration of CC-CDs attenuates synovial inflammation, reduces histological OA severity, preserves proteoglycan-rich cartilage architecture, and inhibits extracellular matrix degradation. Mechanistically, CC-CDs alleviate OA progression by suppressing TLR4/NF-κB signaling, as evidenced by reduced TLR4 expression and p65 phosphorylation. This study highlights bioactive precursor-engineered antioxidant carbon dots as promising nanomedicines and offers a microenvironment-oriented strategy for cartilage preservation and degenerative joint disease intervention.