Abstract
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.
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Acknowledgements
Images were created using BioRender.com, the PyMOL Molecular Graphics System version 2.0 (Schrödinger, LLC) and Avogadro (an open-source molecular builder and visualization tool, version 1.2.0, http://avogadro.cc/). We acknowledge the use of OpenAI’s ChatGPT (version GPT-4) for proofreading the manuscript. D.S. acknowledges support from start-up funds from The University of Texas at Austin and the Welch Foundation (grant no. F-2209-20240404). Y.L. thanks the US National Institute of Health (GM141931) and the Welch Foundation (F-0020) for support. P.S.D. is supported by NSF grant CBET-1936696.
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S.B.E. and D.S. conceived the Perspective. S.B.E. and D.S. wrote the paper with input from H.B., S.S., D.F., P.S.D. and Y.L. S.B.E. and D.S. created the figures and tables. All authors reviewed and edited each section of the paper.
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Ebrahimi, S.B., Bhattacharjee, H., Sonti, S. et al. Engineering considerations for next-generation oligonucleotide therapeutics. Nat Chem Eng 1, 741–750 (2024). https://doi.org/10.1038/s44286-024-00152-z
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DOI: https://doi.org/10.1038/s44286-024-00152-z
