Beyond inflammation: siRNA strategies for precision targeting in rheumatological disorders.

Complex systemic immune dysregulation and chronic inflammation in rheumatological diseases lead to long-term inflammation and morbidity, which are primarily controlled by systemic immunosuppressant agents with diverse effects, underscoring the need for more precise and innovative treatments. The unmatched specificity in targeting disease-driving genes and pathways makes small interfering RNA (siRNA) a transformative treatment approach. This review examines how siRNA can precisely transform the therapy of rheumatological diseases by targeting critical molecular pathways associated with inflammation, immunological dysregulation, and tissue damage. While this study elucidates siRNA therapies targeting inflammatory pathways to treat rheumatological diseases, it moves beyond the conventional therapeutic application of siRNAs targeting pro-inflammatory cytokines; it explicitly focuses on upstream signaling hubs within synovial fibroblasts, T cells, and plasma cells, as well as on non-inflammatory mechanisms that lead to bone damage. The review also integrates in vitro and in vivo, as well as preclinical siRNA studies, to identify the most promising targets and determine whether these siRNA modifications, combined with delivery systems, achieve body-wide and joint-specific immune-stromal network reprogramming through targeted delivery without causing total immune system breakdown.