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Strategies to reduce the risks of mRNA drug and vaccine toxicity

Nature Reviews Drug Discovery volume 23, pages 281–300 (2024)Cite this article

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Abstract

mRNA formulated with lipid nanoparticles is a transformative technology that has enabled the rapid development and administration of billions of coronavirus disease 2019 (COVID-19) vaccine doses worldwide. However, avoiding unacceptable toxicity with mRNA drugs and vaccines presents challenges. Lipid nanoparticle structural components, production methods, route of administration and proteins produced from complexed mRNAs all present toxicity concerns. Here, we discuss these concerns, specifically how cell tropism and tissue distribution of mRNA and lipid nanoparticles can lead to toxicity, and their possible reactogenicity. We focus on adverse events from mRNA applications for protein replacement and gene editing therapies as well as vaccines, tracing common biochemical and cellular pathways. The potential and limitations of existing models and tools used to screen for on-target efficacy and de-risk off-target toxicity, including in vivo and next-generation in vitro models, are also discussed.

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Fig. 1: Innate immune responses to unmodified IVT mRNA.
Fig. 2: Cytokine release as a response to LNP-formulated modified IVT mRNA.
Fig. 3: LNP–mRNA activates the inflammasome.
Fig. 4: PEGylated LNP–mRNAs raise adaptive immune responses in the spleen.

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Author notes

  1. Maximillian A. Rogers

    Present address: Intellia Therapeutics, Cambridge, MA, USA

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA

    Dimitrios Bitounis

  2. Moderna, Inc., Cambridge, MA, USA

    Dimitrios Bitounis, Eric Jacquinet & Maximillian A. Rogers

  3. Departments of Pharmaceutical Sciences and Chemical Engineering, Northeastern University, Boston, MA, USA

    Mansoor M. Amiji

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Correspondence to Mansoor M. Amiji.

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E.J. is employed by Moderna, Inc. D.B. is a Northeastern University post-doctoral fellow with a Moderna, Inc.-sponsored fellowship. M.A.R. is currently affiliated with Intellia Therapeutics, but completed this review while working at Moderna.

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Glossary

Adjuvanticity

The property of certain substances to enhance the immune response against an antigen, thereby improving the effectiveness of vaccines.

Biomolecular corona

A layer of proteins, lipids and small molecules that forms on the surface of nanoparticles when they interact with biological fluids, influencing their biological identity and activity.

Drug-induced liver injury

Liver damage caused by medications or other xenobiotics, which ranges from small abnormalities in liver tests to severe liver dysfunction or failure.

Ionizable lipids

Lipids that remain neutral at physiological pH but are protonated at low pH and are commonly used in the formulation of lipid nanoparticles for RNA delivery.

Lipid nanoparticles

Nanoparticles made of ionizable and other types of lipid, often used as delivery vehicles for genetic material.

MicroRNAs

Small, non-coding, endogenous RNA molecules that regulate protein synthesis by binding to and destroying specific mRNA, thus inhibiting its translation.

Pattern recognition receptors

Proteins that recognize molecules found in pathogens or released because of cellular damage and that can regulate the innate immune response of cells.

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Bitounis, D., Jacquinet, E., Rogers, M.A. et al. Strategies to reduce the risks of mRNA drug and vaccine toxicity. Nat Rev Drug Discov 23, 281–300 (2024). https://doi.org/10.1038/s41573-023-00859-3

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