NatureJun 24, 2026

How mRNA vaccines activate the immune system to fight infections

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 25, 2026

Abstract

Nucleoside-modified mRNA-lipid-nanoparticle vaccines have saved millions of lives since their introduction in 2020.

These vaccines induce strong innate and adaptive immune responses.
A thorough understanding of their mechanisms is essential for developing enhanced mRNA vaccines.
Key knowledge gaps include how lipid nanoparticles are recognized by the immune system and their role as immune boosters.
Identifying specific signals and pathways involved in protective immune responses is still needed.
There is potential to separate vaccine effectiveness from side effects through modifications of the vaccine components.

Simplified

Nucleoside-modified mRNA-lipid-nanoparticle (mRNA-LNP) vaccines confer a high level of protection against severe COVID-19 and, since their first authorization for human use in 2020, have saved millions of lives. The efficacy of this vaccine platform relies on the induction of powerful and coordinated innate and adaptive immune responses. A deep understanding of the mechanisms of action by which mRNA-LNP vaccines drive protective immunity is crucial for advancing the development of next-generation mRNA vaccines with improved immunogenicity and tolerability. A flurry of recent studies has shed light on aspects of this vaccine modality's modus operandi. Nonetheless, key gaps in knowledge remain, including understanding how LNPs are sensed by the immune system and exert their adjuvant activity, identifying the specific signals and cellular pathways critical for eliciting protective immune responses and determining whether it is feasible to uncouple vaccine immunogenicity and reactogenicity. Here we review the known and unknown features of the immunological mechanisms of mRNA-LNP vaccines for infectious diseases. Furthermore, we discuss how the components of this vaccine platform can be modified to fine-tune immune responses against challenging pathogens for which effective vaccines do not exist or need improvement.

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Competing interests

Competing interests: N.P. is named on patents describing the use of nucleoside-modified mRNA in lipid nanoparticles as a vaccine platform; he has disclosed those interests fully to the University of Pennsylvania, and he has in place an approved plan for managing any potential conflicts arising from licensing of those patents. N.P. served on the mRNA strategic advisory board of Sanofi Pasteur in 2022, Pfizer in 2023–2024 and AldexChem in 2023–2025; is a member of the scientific advisory board of BioNet; and has consulted for Vaccine Company, Piezo Therapeutics and Pasture Bio. M.L. declares no competing interests.

PubMed

How mRNA vaccines activate the immune system to fight infections

Abstract

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Competing interests

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