Deng Caifeng, Xiao Yongbing, Zhao Xuan, Li Hui, Chen Yuxiao, Ai Kelong, Jiang Ting, Wei Jie, Chen Xiaoyuan, Lei Guanghua, Zeng Chao
Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Adv Sci (Weinh). 2025 Mar;12(9):e2411911. doi: 10.1002/advs.202411911. Epub 2025 Jan 10.
The infiltration and excessive polarization of M1 macrophages contribute to the induction and persistence of low-grade inflammation in joint-related degenerative diseases such as osteoarthritis (OA). The lipid metabolism dysregulation promotes M1 macrophage polarization by coordinating the compensatory pathways of the inflammatory and oxidative stress responses. Here, a self-assembling, licofelone-loaded nanoparticle (termed LCF-CSBN), comprising chondroitin sulfate and bilirubin joined by an ethylenediamine linker, is developed to selectively reprogram lipid metabolism in macrophage activation. LCF-CSBN is internalized by M1 macrophages via CD44-mediated endocytosis and targets the Golgi apparatus accompanied with the reactive oxygen species-responsive release of licofelone (LCF, dual inhibitor of arachidonic acid metabolism). LCF-CSBN effectively promotes M1 to M2 macrophage transition by reprogramming the Golgi apparatus-related sphingolipid metabolism and arachidonic acid metabolism. Intra-articularly injected LCF-CSBN retains in the joint for up to 28 days and accumulates into M1 macrophages. Moreover, LCF-CSBN can effectively attenuate joint inflammation, oxidative stress, and cartilage degeneration in OA model rats. These findings indicate the promising potential of lipid-metabolism-reprogramming LCF-CSBN in the targeted therapy of OA.
M1巨噬细胞的浸润和过度极化有助于骨关节炎（OA）等关节相关退行性疾病中低度炎症的诱导和持续存在。脂质代谢失调通过协调炎症和氧化应激反应的代偿途径促进M1巨噬细胞极化。在此，开发了一种自组装的、负载利考非酮的纳米颗粒（称为LCF-CSBN），其由硫酸软骨素和胆红素通过乙二胺连接子连接而成，用于在巨噬细胞激活过程中选择性地重新编程脂质代谢。LCF-CSBN通过CD44介导的内吞作用被M1巨噬细胞内化，并靶向高尔基体，同时伴随着利考非酮（LCF，花生四烯酸代谢的双重抑制剂）的活性氧响应性释放。LCF-CSBN通过重新编程与高尔基体相关的鞘脂代谢和花生四烯酸代谢，有效地促进M1向M2巨噬细胞转变。关节内注射的LCF-CSBN在关节中保留长达28天，并积聚到M1巨噬细胞中。此外，LCF-CSBN可以有效减轻OA模型大鼠的关节炎症、氧化应激和软骨退变。这些发现表明，重新编程脂质代谢的LCF-CSBN在OA的靶向治疗中具有广阔的应用前景。
