Delivery of Oligonucleotide Therapeutics: Chemical Modifications, Lipid Nanoparticles, and Extracellular Vesicles
Review article, 2021

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.

intracellular trafficking

endosomal escape

RNA therapeutics

cellular uptake

extracellular vesicles

oligonucleotide delivery

oligonucleotide

lipid nanoparticles

Author

Jeremy P. Bost

Karolinska Institutet

Hanna Barriga

Karolinska Institutet

Margaret N. Holme

Karolinska Institutet

Audrey Gallud

AstraZeneca AB

Chalmers, Biology and Biological Engineering, Chemical Biology

Marco Maugeri

University of Gothenburg

Dhanu Gupta

Karolinska Institutet

Taavi Lehto

University of Tartu

Karolinska Institutet

Hadi Valadi

University of Gothenburg

Elin Esbjörner Winters

Chalmers, Biology and Biological Engineering, Chemical Biology

Molly M. Stevens

Imperial College London

Karolinska Institutet

Samir El-Andaloussi

Karolinska Institutet

ACS Nano

1936-0851 (ISSN) 1936-086X (eISSN)

Vol. 15 9 13993-14021

Subject Categories

Cell Biology

Biochemistry and Molecular Biology

Cell and Molecular Biology

DOI

10.1021/acsnano.1c05099

PubMed

34505766

More information

Latest update

10/12/2021