RNAi-Loaded Nanocarriers Targeting the IL-6/JAK-STAT3-NF-κB Cytokine Axis in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovial inflammation, progressive cartilage degradation, and bone erosion driven by complex cytokine-mediated signaling networks. Central to its pathogenesis is the dysregulated interplay of the interleukin-6 (IL-6)/Janus kinase (JAK)-signal transducer and activator of transcription-3 (STAT3) and nuclear factor kappa-B (NF-κB) pathways, which coordinate transcription of pro-inflammatory cytokines, angiogenic mediators, and osteoclastogenic factors. Conventional therapeutic strategies, including biologics and small-molecule inhibitors, primarily target extracellular mediators and often fail to adequately suppress intracellular signaling redundancy, leading to incomplete or transient clinical responses. RNA interference (RNAi) has emerged as a promising gene-silencing approach capable of selectively downregulating disease-driving transcripts at the post-transcriptional level. However, the clinical translation of RNAi is limited by instability, poor cellular uptake, and rapid degradation of naked small interfering RNA (siRNA). Nanocarrier-based delivery systems provide a transformative solution by protecting siRNA, enhancing pharmacokinetics, enabling targeted delivery to pathogenic cells, and facilitating cytoplasmic release through stimuli-responsive mechanisms. These RNAi-loaded nanoplatforms can simultaneously modulate multiple inflammatory nodes, reprogram immune-cell behavior, attenuate oxidative stress, and inhibit osteoclast genesis, thereby addressing RA as a systems-level disease. Furthermore, advances in precision targeting and multifunctional nanotechnology highlight the broader applicability of this strategy to other cytokine-driven disorders. Despite existing translational challenges, RNAi nanomedicine represents a paradigm shift toward network-oriented, gene-level therapeutics with the potential to achieve durable immunomodulation and disease modification in rheumatoid arthritis. Keywords: Inflammation; JAK-STAT3 signaling; nanocarriers; NF-κB; RNA interference; rheumatoid arthritis