The increasing number of approved nucleic acid therapeutics demonstrates the potential to treat diseases by targeting their genetic blueprints in vivo. Conventional treatments generally induce therapeutic effects that are transient because they target proteins rather than underlying causes. In contrast, nucleic acid therapeutics can achieve long-lasting or even curative effects via gene inhibition, addition, replacement or editing. Their clinical translation, however, depends on delivery technologies that improve stability, facilitate internalization and increase target affinity. Here, we review four platform technologies that have enabled the clinical translation of nucleic acid therapeutics: antisense oligonucleotides, ligand-modified small interfering RNA conjugates, lipid nanoparticles and adeno-associated virus vectors. For each platform, we discuss the current state-of-the-art clinical approaches, explain the rationale behind its development, highlight technological aspects that facilitated clinical translation and provide an example of a clinically relevant genetic drug. In addition, we discuss how these technologies enable the development of cutting-edge genetic drugs, such as tissue-specific nucleic acid bioconjugates, messenger RNA and gene-editing therapeutics.

越来越多的已获批准的核酸疗法证明了通过在体内靶向其基因蓝图来治疗疾病的潜力。常规治疗通常会产生短暂的治疗效果，因为它们针对的是蛋白质而不是根本原因。相比之下，核酸疗法可以通过基因抑制、添加、替换或编辑实现持久甚至治愈的效果。然而，它们的临床转化依赖于提高稳定性、促进内化和增加目标亲和力的递送技术。在这里，我们回顾了实现核酸治疗临床转化的四种平台技术：反义寡核苷酸、配体修饰的小干扰 RNA 偶联物、脂质纳米颗粒和腺相关病毒载体。对于每个平台，我们讨论了当前最先进的临床方法，解释了其开发背后的基本原理，强调了促进临床转化的技术方面，并提供了临床相关基因药物的例子。此外，我们还讨论了这些技术如何促进尖端基因药物的开发，例如组织特异性核酸生物偶联物、信使 RNA 和基因编辑疗法。