Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA.
Adv Drug Deliv Rev. 2023 Oct;201:115052. doi: 10.1016/j.addr.2023.115052. Epub 2023 Aug 9.
Small interfering RNAs (siRNAs) are among the most promising therapeutic platforms in many life-threatening diseases. Owing to the significant advances in siRNA design, many challenges in the stability, specificity and delivery of siRNA have been addressed. However, safety concerns and dose-limiting toxicities still stand among the reasons for the failure of clinical trials of potent siRNA therapies, calling for a need of more comprehensive understanding of their potential mechanisms of toxicity. This review delves into the intrinsic and delivery related toxicity mechanisms of siRNA drugs and takes a holistic look at the safety failure of the clinical trials to identify the underlying causes of toxicity. In the end, the current challenges, and potential solutions for the safety assessment and high throughput screening of investigational siRNA and delivery systems as well as considerations for design strategies of safer siRNA therapeutics are outlined.
小干扰 RNA（siRNA）是许多危及生命的疾病中最有前途的治疗平台之一。由于 siRNA 设计的重大进展，siRNA 的稳定性、特异性和递送方面的许多挑战都得到了解决。然而，安全问题和剂量限制毒性仍然是有效 siRNA 疗法临床试验失败的原因之一，这需要更全面地了解其潜在的毒性机制。本综述深入探讨了 siRNA 药物的内在和递送相关毒性机制，并全面审视了临床试验的安全性失败，以确定毒性的根本原因。最后，概述了用于研究性 siRNA 和递送系统的安全性评估和高通量筛选的当前挑战和潜在解决方案，以及更安全的 siRNA 治疗药物设计策略的考虑因素。
