Engineering considerations for next-generation oligonucleotide therapeutics

Oligonucleotide therapeutics are revolutionizing disease treatment by regulating molecules at the genetic level, offering the possibility of treating conditions that were once considered ‘undruggable’. However, delivering oligonucleotides to tissues beyond the liver remains a key challenge, limiting their clinical applications thus far to niche indications. To achieve broader applicability, extensive biomolecular engineering is necessary to enhance the stability, tissue targetability, pharmacokinetics and pharmacodynamics of these structures. The intricate design of these molecules also demands sophisticated process-engineering techniques. Here we provide a collaborative Perspective from academia and industry on the pivotal role of chemical engineering in expanding the use of therapeutic oligonucleotides to treat a wider range of diseases. We discuss how the interplay between biomolecular and process engineering impacts the developability of next-generation oligonucleotide therapeutics as well as their translation from bench to bedside. Oligonucleotide therapeutics have emerged as a promising alternative to traditional small-molecule and protein-based drugs. This Perspective discusses how chemical engineering can broaden oligonucleotide applications to extrahepatic diseases and enable larger-scale production, ultimately allowing treatment of more prevalent conditions than is currently possible.