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Oligonucleotides - short DNA or RNA molecules - have great therapeutic application for a range of diseases. Yet, their potential has not been fully unleashed because of challenges linked to efficient delivery. Read more to find out about recent developments in oligonucleotide modifications, and the platforms that may be used to deliver them to target sites.

A pair of gloved hands arranging Eppendorf tubes on a rack in a laboratory setting. © Image by Belova59 from Pixabay

Oligonucleotide drugs have enormous potential to transform healthcare via the development of novel precision and/or personalized medicines for a plethora of unmet clinical needs. These include the neurodegeneration, rare diseases, cancers, viral infection, and disorders associated with ageing. Such oligonucleotide therapeutic modalities include gene silencing (e.g. by siRNA or gapmer oligonucleotides), modification of RNA processing (e.g. splice modulation using steric block oligonucleotides), gene activation, non-coding RNA inhibition, aptamers (which interact directly with a target protein), and genome editing using programmable nucleases (e.g. CRISPR-Cas9). Importantly, oligonucleotide-based therapeutics approaches are now reaching maturity, with ten drugs now approved by the US FDA. Many of these high-profile successes are limited to either local administration (e.g. to the eye or spinal cord) or delivery to liver after systemic injection. Indeed, the major hurdle to the development of oligonucleotide therapeutics is effective delivery of these molecules to their target tissues, cells, and sub-cellular sites of action. In the current issue of Nature Reviews Drug Discovery Dr Thomas Roberts and Professor Matthew Wood (from the Department of Paediatrics), together with Professor Robert Langer (MIT), discuss recent advances in oligonucleotide drugs delivery. This review provides an overview of oligonucleotide drug mechanisms of action and the plethora of chemical modifications which impart drug-like properties on these molecules. Established delivery strategies are discussed such as lipid nanoparticles and GalNAc bioconjugates (which both primarily target the liver), in addition to promising technologies being developed including exosomes, spherical nucleic acids, DNA nanostructures, and antibody conjugates.

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