Development of bioconjugate-based delivery systems for nucleic acids.

IF 4.2 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY RNA Pub Date : 2024-10-30 DOI:10.1261/rna.080273.124
Aniket Wahane, Vishal Kasina, Mounika Pathuri, Ciara Marro-Wilson, Anisha Gupta, Frank J Slack, Raman Bahal
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Abstract

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 N-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.

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开发基于生物共轭物的核酸输送系统。
核酸是一类可通过各种机制(即 RNAi、RNase H 裂解降解 mRNA、剪接调节、立体阻断蛋白质结合或 mRNA 翻译)调节基因和蛋白质表达的药物,因此在治疗各种遗传病和罕见病方面具有巨大潜力。与蛋白质靶向疗法不同,核酸的临床应用依赖于沃森-克里克(Watson-Crick)序列识别来调节异常基因表达和阻碍蛋白质翻译。尽管前景广阔,但靶向递送仍是核酸疗法临床应用的瓶颈。为了克服与核酸相关的递送难题,人们探索了各种基于化学修饰和生物共轭的递送策略。目前,N-乙酰半乳糖胺(GalNAc)共轭的肝脏靶向技术已成为治疗罕见病和各种代谢性疾病的前沿技术,美国食品及药物管理局已批准了四种核酸药物。此外,人们还探索了其他各种生物共轭策略,以促进活性器官和细胞靶向。本综述简要介绍了不同类别的核酸、其作用机制和面临的挑战。我们还详细介绍了生物共轭策略在开发用于核酸药物靶向递送的各种配体方面的最新进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
RNA
RNA 生物-生化与分子生物学
CiteScore
8.30
自引率
2.20%
发文量
101
审稿时长
2.6 months
期刊介绍: RNA is a monthly journal which provides rapid publication of significant original research in all areas of RNA structure and function in eukaryotic, prokaryotic, and viral systems. It covers a broad range of subjects in RNA research, including: structural analysis by biochemical or biophysical means; mRNA structure, function and biogenesis; alternative processing: cis-acting elements and trans-acting factors; ribosome structure and function; translational control; RNA catalysis; tRNA structure, function, biogenesis and identity; RNA editing; rRNA structure, function and biogenesis; RNA transport and localization; regulatory RNAs; large and small RNP structure, function and biogenesis; viral RNA metabolism; RNA stability and turnover; in vitro evolution; and RNA chemistry.
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