RNA医学时代已经成为现实，随着mRNA疫苗对抗COVID-19的成功以及近年来多个RNA干扰(RNAi)制剂的批准。特别是基于RNAi的治疗方案提供了以往难以治疗和无法治疗的疾病基因的希望。最近的进展集中在开发传递系统，以增强RNAi治疗的细胞吸收不良和药代动力学性能不足，从而提高其疗效和安全性。然而，这种方法主要通过脂质纳米粒(LNPs)或与N-乙酰半乳糖胺(GalNAc)的化学共轭来实现，因此当前RNAi疗法仅局限于肝脏疾病，最可能遇到肝靶向限制。因此，在RNAi治疗的传递系统方面，对于靶向肝外组织和最终扩大适应症以治疗各种难以治疗的疾病存在巨大的未满足医疗需求。本综述讨论了将RNAi治疗传递至肿瘤和主要器官的挑战，以及它们向临床试验的过渡。本综述还重点介绍了用于治疗肝外疾病的创新且有前景的RNAi基于传递平台。版权 © 2023. Elsevier B.V.出版。

The era of RNA medicine has become a reality with the success of messenger RNA (mRNA) vaccines against COVID-19 and the approval of several RNA interference (RNAi) agents in recent years. Particularly, therapeutics based on RNAi offer the promise of targeting intractable and previously undruggable disease genes. Recent advances have focused in developing delivery systems to enhance the poor cellular uptake and insufficient pharmacokinetic properties of RNAi therapeutics and thereby improve its efficacy and safety. However, such approach has been mainly achieved via lipid nanoparticles (LNPs) or chemical conjugation with N-Acetylgalactosamine (GalNAc), thus current RNAi therapy has been limited to liver diseases, most likely to encounter liver-targeting limitations. Hence, there is a huge unmet medical need for intense evolution of RNAi therapeutics delivery systems to target extrahepatic tissues and ultimately extend their indications for treating various intractable diseases. In this review, challenges of delivering RNAi therapeutics to tumors and major organs are discussed, as well as their transition to clinical trials. This review also highlights innovative and promising preclinical RNAi-based delivery platforms for the treatment of extrahepatic diseases.Copyright © 2023. Published by Elsevier B.V.