Delivery of oligonucleotide therapeutics: chemical modifications, lipid nanoparticles, and extracellular vesicles
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Oligonucleotides (ONs) comprise a rapidly growing class of therapeutics. In recent years, the list of FDA-approved ON therapies has rapidly expanded. ONs are small (15–30 bp) nucleotide-based therapeutics which are capable of targeting DNA and RNA as well as other biomolecules. ONs can be subdivided into several classes based on their chemical modifications and on the mechanisms of their target interactions. Historically, the largest hindrance to the widespread usage of ON therapeutics has been their inability to effectively internalize into cells and escape from endosomes to reach their molecular targets in the cytosol or nucleus. While cell uptake has been improved, “endosomal escape” remains a significant problem. There are a range of approaches to overcome this, and in this review, we focus on three: altering the chemical structure of the ONs, formulating synthetic, lipid-based nanoparticles to encapsulate the ONs, or biologically loading the ONs into extracellular vesicles. This review provides a background to the design and mode of action of existing FDA-approved ONs. It presents the most common ON classifications and chemical modifications from a fundamental scientific perspective and provides a roadmap of the cellular uptake pathways by which ONs are trafficked. Finally, this review delves into each of the above-mentioned approaches to ON delivery, highlighting the scientific principles behind each and covering recent advances.
Date Issued
2021-09-28
Date Acceptance
2021-09-01
Citation
ACS Nano, 2021, 15 (9), pp.13993-14021
ISSN
1936-0851
Publisher
American Chemical Society
Start Page
13993
End Page
14021
Journal / Book Title
ACS Nano
Volume
15
Issue
9
Copyright Statement
© 2021 The Authors. Published by American Chemical Society. This work is published under CC BY 4.0 Internationa license.
License URL
Sponsor
Royal Academy Of Engineering
Medical Research Council (MRC)
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000703553600007&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
CIET2021\94
MR/R015651/1
Subjects
Science & Technology
Physical Sciences
Technology
Chemistry, Multidisciplinary
Chemistry, Physical
Nanoscience & Nanotechnology
Materials Science, Multidisciplinary
Chemistry
Science & Technology - Other Topics
Materials Science
oligonucleotide
oligonucleotide delivery
intracellular trafficking
endosomal escape
RNA therapeutics
lipid nanoparticles
extracellular vesicles
cellular uptake
DUCHENNE MUSCULAR-DYSTROPHY
RNAI-BASED NANOMEDICINES
RECEPTOR-MEDIATED UPTAKE
SMALL ORGANIC-COMPOUNDS
LOCKED NUCLEIC-ACID
MESSENGER-RNA
IN-VIVO
CATIONIC LIPIDS
SIRNA DELIVERY
ANTISENSE OLIGONUCLEOTIDES
Publication Status
Published
Date Publish Online
2021-09-10