siRNA疗法已获得广泛关注，迄今为止已有六种siRNA被批准用于临床。尽管正在研究其用于治疗代谢、心血管、传染性和罕见遗传疾病、癌症和中枢神经系统（CNS）疾病，但仍存在一些成药性挑战。在这里，我们对这些挑战进行了深入的讨论，包括靶向积累和细胞摄取（“进入”）、内溶酶体逃逸（“逃逸”）和体内药物性能（“功效”）——三个“E”挑战——同时也为 siRNA 药物开发提供线索。此外，我们提出了几种有前景的策略，这些策略在促进 siRNA 疗法的临床转化方面具有巨大潜力，包括探索不同的配体-siRNA 缀合物、扩展潜在的疾病靶点、挖掘新的修饰几何结构以及开发组合药物版权所有 © 2023 Elsevier Ltd. 保留所有权利。

siRNA therapeutics have gained extensive attention, and to date six siRNAs are approved for clinical use. Despite being investigated for the treatment of metabolic, cardiovascular, infectious, and rare genetic diseases, cancer, and central nervous system (CNS) disorders, there exist several druggability challenges. Here, we provide insightful discussions concerning these challenges, comprising targeted accumulation and cellular uptake ('entry'), endolysosomal escape ('escape'), and in vivo pharmaceutical performance ('efficacy') - the three 'E' challenges - while also shedding light on siRNA drug development. Moreover, we propose several promising strategies that hold great potential in facilitating the clinical translation of siRNA therapeutics, including the exploration of diverse ligand-siRNA conjugates, expansion of potential disease targets, and excavation of novel modification geometries, as well as the development of combination therapies.Copyright © 2023 Elsevier Ltd. All rights reserved.