Shan Yu, Zhao Jianan, Wei Kai, Jiang Ping, Shi Yiming, Chang Cen, Zheng Yixin, Zhao Fuyu, Li Yunshen, He Bingheng, Zhou Mi, Liu Jia, Li Li, Guo Shicheng, He Dongyi
Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China; The Research Institute for Joint Diseases, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China.
Department of rehabilitation, Tongren Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Int Immunopharmacol. 2025 Jun 26;159:114890. doi: 10.1016/j.intimp.2025.114890. Epub 2025 May 19.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic joint inflammation. Existing therapeutic regimens, including disease-modifying anti-rheumatic drugs (DMARDs) and biologics, exhibit incomplete efficacy and pronounced limitations. RNA interference (RNAi) utilizing small interfering RNA (siRNA) facilitates the precise silencing of key pathological drivers in rheumatoid arthritis (RA), such as tumor necrosis factor-alpha (TNF-α), interleukins IL-1 and IL-6, as well as pivotal inflammatory pathways including NF-κB. This comprehensive systematic review meticulously analyzes 140 studies focusing on therapeutic siRNA for RA. The utilization of siRNA in RA involves the profound inhibition of macrophage and fibroblast-like synoviocyte (FLS) activation through the strategic targeting of TNF, RELA, and MAPK/JAK signaling pathways. In addition, siRNA diminishes inflammatory responses by suppressing critical inflammasome constituents like NLRP3 and fosters the reestablishment of immune equilibrium via downregulation of Th17 differentiation factors and augmentation of regulatory T cell (Treg) functions. It also directly reduces the aggressiveness of FLS by inhibiting pathological signaling components such as CCN1, KHDRBS1 and E2F2. Experimental studies in rodent models have demonstrated that targeted delivery of siRNA via nanoparticles against pathogenic mediators significantly suppresses paw inflammation and mitigates joint destruction. Although challenges such as stability, off-target effects, and efficient delivery remain, advancements in molecular modifications and nanoparticle technology offer promising solutions to these obstacles. In conclusion, unlike the traditional single-target DMARDs or biologics, multi-target RNA interference presents a highly precise mechanism to inhibit intracellular inflammatory cascade and joint damage progression in RA, offering a potential deterrent to disease advancement.
类风湿性关节炎（RA）是一种以慢性关节炎症为特征的自身免疫性疾病。现有的治疗方案，包括改善病情抗风湿药（DMARDs）和生物制剂，疗效并不完全，且存在明显局限性。利用小干扰RNA（siRNA）的RNA干扰（RNAi）技术有助于精确沉默类风湿性关节炎（RA）中的关键病理驱动因素，如肿瘤坏死因子-α（TNF-α）、白细胞介素IL-1和IL-6，以及包括核因子κB（NF-κB）在内的关键炎症信号通路。这篇全面的系统综述精心分析了140项聚焦于RA治疗性siRNA的研究。在RA中使用siRNA涉及通过对TNF、RELA和MAPK/JAK信号通路进行策略性靶向，深度抑制巨噬细胞和成纤维细胞样滑膜细胞（FLS）的活化。此外，siRNA通过抑制关键的炎性小体成分（如NLRP3）来减少炎症反应，并通过下调Th17分化因子和增强调节性T细胞（Treg）功能来促进免疫平衡的重建。它还通过抑制CCN1、KHDRBS1和E2F2等病理信号成分，直接降低FLS的侵袭性。在啮齿动物模型中的实验研究表明，通过纳米颗粒靶向递送siRNA对抗致病介质可显著抑制爪部炎症并减轻关节破坏。尽管仍存在稳定性、脱靶效应和有效递送等挑战，但分子修饰和纳米颗粒技术的进展为克服这些障碍提供了有前景的解决方案。总之，与传统的单靶点DMARDs或生物制剂不同，多靶点RNA干扰呈现出一种高度精确的机制，可抑制RA中的细胞内炎症级联反应和关节损伤进展，为疾病进展提供了潜在的抑制作用。
