More than 25 years after its discovery, the post-transcriptional gene regulation mechanism termed RNAi is now transforming pharmaceutical development, proved by the recent FDA approval of multiple small interfering RNA (siRNA) drugs that target the liver. Synthetic siRNAs that trigger RNAi have the potential to specifically silence virtually any therapeutic target with unprecedented potency and durability. Bringing this innovative class of medicines to patients, however, has been riddled with substantial challenges, with delivery issues at the forefront. Several classes of siRNA drug are under clinical evaluation, but their utility in treating extrahepatic diseases remains limited, demanding continued innovation. In this Review, we discuss principal considerations and future directions in the design of therapeutic siRNAs, with a particular emphasis on chemistry, the application of informatics, delivery strategies and the importance of careful target selection, which together influence therapeutic success.

在其发现超过 25 年之后，被称为 RNAi 的转录后基因调控机制现在正在改变药物开发，FDA 最近批准了多种针对肝脏的小干扰 RNA (siRNA) 药物就证明了这一点。触发 RNAi 的合成 siRNA 有可能以前所未有的效力和持久性特异性沉默几乎任何治疗靶点。然而，将这类创新药物带给患者却面临着巨大的挑战，其中最重要的是交付问题。几类 siRNA 药物正在临床评估中，但它们在治疗肝外疾病方面的效用仍然有限，需要持续创新。在这篇综述中，我们讨论了治疗性 siRNA 设计的主要考虑因素和未来方向，特别强调化学、信息学的应用、递送策略和仔细靶标选择的重要性，这些共同影响治疗的成功。