Exploring the advances and challenges in the delivery of oligonucleotide therapeutics

“One challenge we face as a field is that it is hard to learn from our peers because oftentimes, all you see is, ‘Hey, we went from delivery system X to Y,’ and you see an increase in on-target delivery, but no mention of off-target effects. Since the first US FDA approval in 1998, 22 oligonucleotide drugs have reached the market, addressing rare, genetic, and other diseases. Today, with nearly 300 ongoing clinical trials and over 2,000 therapies in development, the field is expanding rapidly. Yet, significant challenges remain—foremost among them is delivery. In this article, Kehinde Ross (Associate Professor, Liverpool John Moores University) and James Dahlman (Associate Professor, Georgia Institute of Technology) discuss the key challenges and innovations in oligonucleotide delivery—from tissue targeting, endosomal escape, and nanoparticle design to animal model translation, blood–brain barrier strategies, and equitable global access.