Osteoarthritis (OA), a chronic degenerative joint disease characterized by cartilage breakdown and synovial inflammation, remains clinically intractable due to the lack of disease-modifying therapies. Existing treatments fail to effectively mitigate the pathological microenvironment, which is dominated by excess reactive oxygen species (ROS) and sustained inflammatory responses. Nanozymes have emerged as promising ROS-scavenging agents, yet their therapeutic efficacy is limited by insufficient bioactivity and a lack of immunomodulatory function. Herein, we report a rationally designed metal-polyphenol coordination nanozyme constructed from zinc ions and Loureirin B (LB), termed Zn-LB NPs, which integrates catalytic activity and immunoregulation for OA therapy. The Zn-LB NPs exhibit robust antioxidant capacity, mimicking multiradical scavenging activity via ABTS•+, DPPH•, and PTIO• assays. Importantly, nanoformulation markedly improves the aqueous solubility and bioavailability of LB, a hydrophobic flavonoid with known anti-inflammatory properties but poor pharmacokinetics. Mechanistically, Zn-LB NPs restore mitochondrial function and reduce apoptosis in IL-1β-stimulated chondrocytes, while promoting anabolic gene expression. In parallel, they reprogram RAW264.7 macrophages from an M1 to M2 phenotype, thereby suppressing pro-inflammatory cytokines. In vivo, intra-articular injection of Zn-LB NPs significantly attenuates cartilage degradation, reduces MMP13 and TNF-α expression, and improves locomotor function in MIA-induced OA mice. No significant systemic toxicity was observed in biochemical, hematological, or histological assessments. This dual-function nanozyme platform synergistically addresses oxidative and immune dysregulation in OA, offering a disease-modifying strategy by integrating catalytic therapy with natural drug delivery. Our findings establish Zn-LB NPs as safe and effective nanotherapeutics for cartilage protection and OA intervention.
