A Zinc–Loureirin B Coordination Nanozyme for Oxidative and Inflammatory Microenvironment Remodeling in Osteoarthritis
Zelin Xu, Haoran Yu, Zhongyao Hu, Chen Wang, Zijian Song, Dechao Cai, Bing Ma, Hongliang Ge, Jianbo Fan, Yang Zhu, Wendan Cheng
Abstract
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.