Therapeutic oligonucleotides: the promises are up for delivery

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Dear reader,
This editorial is dedicated to therapeutic oligonucleotides, their existing challenges and how to effectively overcome them. In the OLIGONUCLEOTIDE AND PEPTIDES section of this issue you will in fact find two insights on RNA-based therapies, with historical perspectives and the pivotal role they are expected to have in the future. I would like to start with a bit of history and definitions. After about 40 years of development, RNA medicines now constitute a novel and emerging class of drugs. Most prominent are the two mRNA-based vaccines, BNT162b2 and mRNA-1273 developed by BioNTech/Pfizer and Moderna, respectively, which proved effective in establishing control of the coronavirus disease 2019 (COVID-19). As landmarks of successful science and innovation within the biotech and pharma industries, they have resulted in profound thrust in RNA-based drugs not only within these industries, but also among decision makers and the public. Scientific discoveries made in the preceding years including RNA delivery within lipid nanoparticles, in vivo translation of exogenous mRNA-like molecules, and modifications of RNA nucleotides, have enabled the realization of these efficient vaccines (1). Stimulated by the increasing knowledge gained from RNA research, other types of potential RNA-based medicines have recently moved into development, including CRISPR-Cas based systems, circular RNAs and mRNA molecules in general. These involve relatively long RNA molecules or complex RNA/protein mixtures and can be said to constitute more biology-focused strategies (2).
Oligonucleotides are composed of up to approximately 50 nucleotides. Among the approved and currently used RNA medicines, all, besides the two mRNA COVID-19 vaccines, can be characterized as oligonucleotides. Thus, they are either short interfering double stranded RNAs (siRNAs) or single-stranded antisense-type oligomers (ASOs), with a hand-full of each approved during the last 10 years (3). Both ASOs and siRNAs are inspired by naturally occurring RNAs, but since the first use of a synthetic oligonucleotide to control gene expression in 1978 (4), the use of chemically modified nucleotides has been a foundation for the progress of the field and thus the successful approval of the novel drugs. The remaining part of this editorial will be focused on the current status and immediate future of oligonucleotide-based drugs with particular focus on key structural aspects in relation to delivery and molecular design.