Multi-target RNA interference: A disruptive next-generation strategy for precision treatment of rheumatoid arthritis

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. • This comprehensive review synthesizes current knowledge and explores the future potential of siRNA as a groundbreaking therapeutic technology for precision treatment of rheumatoid arthritis. • It systematically analyzes over 140 studies addressing diverse applications such as inflammatory signaling inhibition, fibroblast suppression, immune modulation, and enhanced delivery. • The review underscores the unique capability of multi-targeting siRNA to precisely silence crucial intracellular drivers of RA pathogenesis. • It details ongoing efforts to address delivery and specificity challenges through chemical modifications and the use of nanocarriers, aiming to facilitate the translation from efficacious preclinical studies to clinical applications. • Overall, the review provides key insights into the significant advantages of therapeutic siRNA silencing strategies in halting RA progression, and it guides further research on this promising next-generation approach for maintaining disease remission.