Therapeutic Oligonucleotides: An Outlook on Chemical Strategies to Improve Endosomal Trafficking

被引：8
作者：
Mangla, Priyanka [1 ]
Vicentini, Quentin [1 ,2 ]
Biscans, Annabelle [1 ]
机构：
[1] AstraZeneca, Oligonucleotide Discovery, Discovery Sci Res & Dev, S-43138 Gothenburg, Sweden
[2] Karolinska Inst, Clin Res Ctr, Dept Lab Med, S-14157 Stockholm, Sweden
来源：
CELLS | 2023年 / 12卷 / 18期
基金：
欧盟地平线“2020”;
关键词：
oligonucleotide therapeutics; antisense oligonucleotides (ASOs); siRNA; oligonucleotide delivery; endosomal escape; endosomolytic agents; oligonucleotide conjugates; linker chemistry; non-cleavable linkers; cleavable linkers; pH-sensitive linkers; CELL-PENETRATING PEPTIDES; IN-VIVO DELIVERY; GENE SILENCING ACTIVITY; ARGININE-RICH PEPTIDES; NUCLEIC-ACIDS; SIRNA DELIVERY; MEDIATED DELIVERY; NONVIRAL VECTORS; ANTISENSE OLIGONUCLEOTIDES; PHYSICOCHEMICAL PROPERTIES;
D O I：
10.3390/cells12182253
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
The potential of oligonucleotide therapeutics is undeniable as more than 15 drugs have been approved to treat various diseases in the liver, central nervous system (CNS), and muscles. However, achieving effective delivery of oligonucleotide therapeutics to specific tissues still remains a major challenge, limiting their widespread use. Chemical modifications play a crucial role to overcome biological barriers to enable efficient oligonucleotide delivery to the tissues/cells of interest. They provide oligonucleotide metabolic stability and confer favourable pharmacokinetic/pharmacodynamic properties. This review focuses on the various chemical approaches implicated in mitigating the delivery problem of oligonucleotides and their limitations. It highlights the importance of linkers in designing oligonucleotide conjugates and discusses their potential role in escaping the endosomal barrier, a bottleneck in the development of oligonucleotide therapeutics.
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页数：38
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