Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing. As such, these molecules have potential therapeutic applications for myriad indications, with several oligonucleotide drugs recently gaining approval. However, despite recent technological advances, achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation. Here, we provide an overview of oligonucleotide-based drug platforms, focusing on key approaches — including chemical modification, bioconjugation and the use of nanocarriers — which aim to address the delivery challenge.

寡核苷酸可用于通过一系列过程调节基因表达，包括 RNAi、通过 RNase H 介导的切割降解靶标、剪接调节、非编码 RNA 抑制、基因激活和程序化基因编辑。因此，这些分子对无数适应症具有潜在的治疗应用，最近有几种寡核苷酸药物获得批准。然而，尽管最近的技术进步，实现有效的寡核苷酸递送，特别是肝外组织，仍然是一个主要的翻译限制。在这里，我们概述了基于寡核苷酸的药物平台，重点关注旨在解决递送挑战的关键方法——包括化学修饰、生物偶联和纳米载体的使用。