Small Interfering Ribonucleic Acid (siRNA)-Based Therapeutics in Inflammatory Bowel Disease: Crosstalk between Immune Modulation and Epithelial Barrier Restoration.

Inflammatory bowel disease is an autoimmune disorder associated with the gastrointestinal tract that includes ulcerative colitis and Crohn's disease, aggravated by dysregulated immune responses, disrupted epithelial barriers, and microbial dysbiosis. Even though there have been improvements in conventional therapies, including corticosteroids, immunomodulators, and biologics, current treatments are still limited by nonspecific action, systemic side effects, and inadequate remission rates. Therapeutics based on small interfering RNA (siRNA) have become a cutting-edge, precision-driven method that can silence particular genes implicated in the pathophysiology of IBD. siRNA primarily reduces mucosal inflammation by silencing proinflammatory cytokines (TNF-α, IL-6, IL-12/23) and downstream signaling mediators (NF-κB, JAK/STAT). According to certain research, it plays a crucial part in immunological homeostasis by polarizing macrophages. Additionally, siRNA targets tight junction proteins such as ZO-1, occludin, and claudin to enhance the function of the mucosal barrier. Combination therapy of siRNA, which involves delivering multiple siRNA or codelivering with cytokines or biologics, is currently being utilized for alleviating IBD and might be further developed in the future. Even though siRNA has made significant advancements as a therapeutic agent, there is still a lack of clinical translation, which will need to be done in the future to ensure its effectiveness and safety. This review, taken as a whole, incorporates recent discoveries about siRNA-mediated immune modulation and barrier restoration, offering an optimistic outlook on how multitargeted, precision RNA therapies may revolutionize the treatment of IBD.