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Tailor made: the art of therapeutic mRNA design

Nature Reviews Drug Discovery volume 23, pages 67–83 (2024)Cite this article

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Abstract

mRNA medicine is a new and rapidly developing field in which the delivery of genetic information in the form of mRNA is used to direct therapeutic protein production in humans. This approach, which allows for the quick and efficient identification and optimization of drug candidates for both large populations and individual patients, has the potential to revolutionize the way we prevent and treat disease. A key feature of mRNA medicines is their high degree of designability, although the design choices involved are complex. Maximizing the production of therapeutic proteins from mRNA medicines requires a thorough understanding of how nucleotide sequence, nucleotide modification and RNA structure interplay to affect translational efficiency and mRNA stability. In this Review, we describe the principles that underlie the physical stability and biological activity of mRNA and emphasize their relevance to the myriad considerations that factor into therapeutic mRNA design.

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Fig. 1: Fundamentals of mRNA medicines.
Fig. 2: Basics of RNA structure.
Fig. 3: Intermediate and final folding states of long RNA molecules.
Fig. 4: Modified nucleotides affect secondary structure.
Fig. 5: Stem–loop structures can modulate mRNA function.
Fig. 6: Viral structural elements that facilitate translation.

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Acknowledgements

The authors thank J. Gilmore for the atomic force microscopy images in Fig. 3i, D. Mauger, I. McFadyen and C. Köhrer for preliminary discussions of this work, and A. Bicknell, D. Reid, K. Loh, J. Zimmer and E. Jankowsky for critical reading of the manuscript. This work was supported by Moderna, Inc.

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    Mihir Metkar, Christopher S. Pepin & Melissa J. Moore

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Metkar, M., Pepin, C.S. & Moore, M.J. Tailor made: the art of therapeutic mRNA design. Nat Rev Drug Discov 23, 67–83 (2024). https://doi.org/10.1038/s41573-023-00827-x

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