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Drug delivery systems for RNA therapeutics

Nature Reviews Genetics volume 23, pages 265–280 (2022)Cite this article

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Abstract

RNA-based gene therapy requires therapeutic RNA to function inside target cells without eliciting unwanted immune responses. RNA can be ferried into cells using non-viral drug delivery systems, which circumvent the limitations of viral delivery vectors. Here, we review the growing number of RNA therapeutic classes, their molecular mechanisms of action, and the design considerations for their respective delivery platforms. We describe polymer-based, lipid-based, and conjugate-based drug delivery systems, differentiating between those that passively and those that actively target specific cell types. Finally, we describe the path from preclinical drug delivery research to clinical approval, highlighting opportunities to improve the efficiency with which new drug delivery systems are discovered.

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Fig. 1: The expanding universe of therapeutic RNA payloads.
Fig. 2: FDA-approved lipid-based structures contain some variation of the four basic components: cholesterol, a helper lipid, a PEG-lipid, and a cationic or ionizable lipid.
Fig. 3: RNA can be delivered using nanoparticles formulated with polymers or dendrimers.
Fig. 4: Drug delivery vehicles can use two mechanisms of action to reach their target cell type.
Fig. 5: The preclinical nanoparticle discovery pipeline.
Fig. 6: The hallmarks of a clinically relevant delivery system.

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Acknowledgements

The authors thank K. Tiegren at the Georgia Institute of Technology for copyediting the manuscript.

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  1. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA

    Kalina Paunovska, David Loughrey & James E. Dahlman

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  1. Kalina Paunovska
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Paunovska, K., Loughrey, D. & Dahlman, J.E. Drug delivery systems for RNA therapeutics. Nat Rev Genet 23, 265–280 (2022). https://doi.org/10.1038/s41576-021-00439-4

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