Therapeutic siRNA: Mechanisms, challenges, strategies, and clinical translation.

RNA interference is an ancient biological defense mechanism against external invasions. Mechanistically, small interfering RNA (siRNA) can specifically bind to any target gene, according to the principle of complementary base pairing, to exert silencing effects. Therefore, siRNA has the potential to serve as an efficient therapeutic agent for various diseases. However, due to their susceptibility to nucleases, off-target effects, and low cellular uptake, the development of siRNA-based drugs remains challenging. Fortunately, with the advancement in chemical modifications and delivery systems, patisiran, the first siRNA therapeutic, was approved for the treatment of hereditary transthyretin amyloidosis by the United States Food and Drug Administration (FDA) in 2018, which represents a crucial milestone in the field of siRNA research. Subsequently, seven other siRNA drugs were introduced to the market. Thus, siRNA drugs are on their way to becoming standard pharmacotherapy tools. This review presents the mechanisms of action, delivery barriers, chemical modifications, and delivery platforms of siRNA. Furthermore, it also summarizes commercialized siRNA drugs and some clinical trials, thereby providing a comprehensive knowledge map of siRNA drug modifications, delivery strategies, action mechanisms, and updated clinical trials.