Cellular uptake and trafficking of antisense oligonucleotides
Abstract
Antisense oligonucleotides (ASOs) modified with phosphorothioate (PS) linkages and different 2' modifications can be used either as drugs (e.g., to treat homozygous familial hypercholesterolemia and spinal muscular atrophy) or as research tools to alter gene expression. PS-ASOs can enter cells without additional modification or formulation and can be designed to mediate sequence-specific cleavage of different types of RNA (including mRNA and non-coding RNA) targeted by endogenous RNase H1. Although PS-ASOs function in both the cytoplasm and nucleus, localization to different subcellular regions can affect their therapeutic potency. Cellular uptake and intracellular distribution of PS ASOs are mediated by protein interactions. The main proteins involved in these processes have been identified, and intracellular sites in which PS ASOs are active, or inactive, cataloged.
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Multiple cell surface receptors have been recently identified that may be involved in phosphorothioate-mediated oligonucleotide uptake.
“The underlying mechanism is not fully understood, but multiple cell surface receptors have been recently identified that may be involved in phosphorothioate-mediated oligonucleotide uptake15.”
From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [15]
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- Authors
- Crooke, S. T., Wang, S., Vickers, T. A., Shen, W., & Liang, X.-H.
- Affiliations
- Ionis Pharmaceuticals (United States) (US)
- Corresponding author
- Crooke, Stanley T
- Venue
- Nature Biotechnology
- Published
- 2017-02-27
- Volume
- 35
- Issue
- 3
- Pages
- 230-237
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W2591728558
- Cited by
- 582
- References
- 1
- Citations by year
- 2026: 57 · 2025: 59 · 2024: 57 · 2023: 71 · 2022: 70 · 2021: 73 · 2020: 62 · 2019: 62 · 2018: 53 · 2017: 18
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ionis Pharmaceuticals
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- antisense oligonucleotides, phosphorothioate linkages, cellular uptake, intracellular trafficking, subcellular localization, protein-protein interaction, RNase H1, RNA cleavage, homozygous familial hypercholesterolemia, spinal muscular atrophy, gene expression modulation
- MeSH terms
- Animals, Cell Membrane, Humans, Structure-Activity Relationship, Subcellular Fractions, Genetic Therapy, Oligonucleotides, Antisense
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