Xu Zelin, Yu Haoran, Hu Zhongyao, Wang Chen, Song Zijian, Cai Dechao, Ma Bing, Ge Hongliang, Fan Jian-Bo, Zhu Yang, Cheng Wendan
Department of Orthopedics, the Second Affiliated Hospital of Anhui Medical University, Hefei 230000, China.
Institute of Orthopedics, Research Center for Translational Medicine, the Second Affiliated Hospital of Anhui Medical University, Hefei 230000, China.
ACS Appl Mater Interfaces. 2025 Sep 10;17(36):50203-50216. doi: 10.1021/acsami.5c07574. Epub 2025 Aug 27.
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.
骨关节炎（OA）是一种以软骨破坏和滑膜炎症为特征的慢性退行性关节疾病，由于缺乏改善病情的疗法，在临床上仍然难以治疗。现有的治疗方法无法有效缓解以过量活性氧（ROS）和持续炎症反应为主导的病理微环境。纳米酶已成为有前景的ROS清除剂，但其治疗效果受到生物活性不足和缺乏免疫调节功能的限制。在此，我们报道了一种由锌离子和龙血素B（LB）构建的合理设计的金属-多酚配位纳米酶，称为Zn-LB NPs，它整合了催化活性和免疫调节功能用于OA治疗。Zn-LB NPs表现出强大的抗氧化能力，通过ABTS•、DPPH•和PTIO•测定模拟多自由基清除活性。重要的是，纳米制剂显著提高了LB的水溶性和生物利用度，LB是一种具有已知抗炎特性但药代动力学较差的疏水性黄酮类化合物。从机制上讲，Zn-LB NPs恢复线粒体功能并减少IL-1β刺激的软骨细胞凋亡，同时促进合成代谢基因表达。同时，它们将RAW264.7巨噬细胞从M1表型重编程为M2表型，从而抑制促炎细胞因子。在体内，关节内注射Zn-LB NPs可显著减轻软骨降解，降低MMP13和TNF-α表达，并改善MIA诱导的OA小鼠的运动功能。在生化、血液学或组织学评估中未观察到明显的全身毒性。这种双功能纳米酶平台协同解决了OA中的氧化和免疫失调问题，通过将催化疗法与天然药物递送相结合提供了一种改善病情的策略。我们的研究结果确立了Zn-LB NPs作为用于软骨保护和OA干预的安全有效的纳米治疗剂。
