Wahane Aniket, Kasina Vishal, Pathuri Mounika, Marro-Wilson Ciara, Gupta Anisha, Slack Frank J, Bahal Raman
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, USA.
Department of Pharmaceutical Sciences, University of Saint Joseph, West Hartford, Connecticut 06033, USA.
RNA. 2024 Dec 16;31(1):1-13. doi: 10.1261/rna.080273.124.
Nucleic acids are a class of drugs that can modulate gene and protein expression by various mechanisms, namely, RNAi, mRNA degradation by RNase H cleavage, splice modulation, and steric blocking of protein binding or mRNA translation, thus exhibiting immense potential to treat various genetic and rare diseases. Unlike protein-targeted therapeutics, the clinical use of nucleic acids relies on Watson-Crick sequence recognition to regulate aberrant gene expression and impede protein translation. Though promising, targeted delivery remains a bottleneck for the clinical adoption of nucleic acid-based therapeutics. To overcome the delivery challenges associated with nucleic acids, various chemical modifications and bioconjugation-based delivery strategies have been explored. Currently, liver targeting by -acetyl galactosamine (GalNAc) conjugation has been at the forefront for the treatment of rare and various metabolic diseases, which has led to FDA approval of four nucleic acid drugs. In addition, various other bioconjugation strategies have been explored to facilitate active organ and cell-enriched targeting. This review briefly covers the different classes of nucleic acids, their mechanisms of action, and their challenges. We also elaborate on recent advances in bioconjugation strategies in developing a diverse set of ligands for targeted delivery of nucleic acid drugs.
核酸是一类能够通过多种机制调节基因和蛋白质表达的药物，这些机制包括RNA干扰、核糖核酸酶H切割导致的信使核糖核酸降解、剪接调节以及蛋白质结合或信使核糖核酸翻译的空间位阻，因此在治疗各种遗传疾病和罕见病方面展现出巨大潜力。与蛋白质靶向治疗药物不同，核酸的临床应用依赖于沃森-克里克序列识别来调节异常基因表达并阻碍蛋白质翻译。尽管前景广阔，但靶向递送仍然是基于核酸的治疗药物临床应用的一个瓶颈。为了克服与核酸相关的递送挑战，人们探索了各种化学修饰和基于生物共轭的递送策略。目前，通过与N-乙酰半乳糖胺（GalNAc）共轭实现肝脏靶向已处于治疗罕见病和各种代谢疾病的前沿，这使得四种核酸药物获得了美国食品药品监督管理局（FDA）的批准。此外，人们还探索了各种其他生物共轭策略，以促进主动靶向富集特定器官和细胞。本综述简要介绍了不同类型的核酸、它们的作用机制以及面临的挑战。我们还详细阐述了在开发用于核酸药物靶向递送的多种配体方面生物共轭策略的最新进展。
