Zhou Kai, Yang Chengli, Shi Kun, Liu Yue, Hu Danrong, He Xinlong, Yang Yun, Chu Bingyang, Peng Jinrong, Zhou Zongke, Qian Zhiyong
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China; Department of Orthopedics, Orthopedic Research Institute, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China; Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
Biomaterials. 2023 Apr;295:122036. doi: 10.1016/j.biomaterials.2023.122036. Epub 2023 Feb 11.
Osteoarthritis (OA) is a common joint condition that is a leading cause of disability worldwide. There are currently no disease-modifying treatments for osteoarthritis, which is associated with multiple kinds of inflammatory cytokines produced by M1 macrophages in the synovium of the joint. Despite recent therapeutic advancements with anti-cytokine biologics, the OA therapy response rate continues to be inadequate. To treat OA, the pro-inflammatory and anti-inflammatory responses of synoviocytes and macrophages must be controlled simultaneously. Therefore, the immune regulation capabilities of an ideal nano-drug should not only minimize pro-inflammatory responses but also effectively boost anti-inflammatory responses. In this paper, an M2H@RPK nanotherapeutic system was developed, KAFAK and shRNA-LEPR were condensed with polyethylenimine (PEI) to form a complex, which was then modified with hyaluronic acid (HA) to negatively charge to cover the M2 membrane. It was discovered that the repolarization of macrophages from the M1 to the M2 phenotype lowered pro-inflammatory responses while enhancing anti-inflammatory responses in macrophages and synoviocytes. In vitro and in vivo studies demonstrate that M2H@RPK dramatically decreases proinflammatory cytokines, controls synovial inflammation, and provides significant therapeutic efficacy by reducing joint damage. Overall, it has been demonstrated that M2H@RPK provides inflammation-targeted therapy by macrophage repolarization, and it represents a promising OA therapeutic strategy.
骨关节炎（OA）是一种常见的关节疾病，是全球致残的主要原因。目前尚无针对骨关节炎的疾病修饰治疗方法，该疾病与关节滑膜中M1巨噬细胞产生的多种炎性细胞因子有关。尽管抗细胞因子生物制剂在近期治疗方面取得了进展，但OA治疗的有效率仍然不足。要治疗OA，必须同时控制滑膜细胞和巨噬细胞的促炎和抗炎反应。因此，理想的纳米药物的免疫调节能力不仅应使促炎反应最小化，还应有效地增强抗炎反应。在本文中，开发了一种M2H@RPK纳米治疗系统，将KAFAK和shRNA-LEPR与聚乙烯亚胺（PEI）缩合形成复合物，然后用透明质酸（HA）进行修饰以带负电荷，从而覆盖M2膜。研究发现，巨噬细胞从M1表型重新极化至M2表型可降低促炎反应，同时增强巨噬细胞和滑膜细胞中的抗炎反应。体外和体内研究表明，M2H@RPK可显著降低促炎细胞因子水平，控制滑膜炎症，并通过减少关节损伤提供显著的治疗效果。总体而言，已证明M2H@RPK通过巨噬细胞重新极化提供炎症靶向治疗，代表了一种有前景的OA治疗策略。
