mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression

Apr 29, 2026Nature biotechnology

mRNA vaccine immunity improves when liver cells are avoided and does not rely on immune cell production

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

mRNA expression in professional antigen-presenting cells is dispensable for priming antigen-specific T cells.

mRNA expression in myocytes may induce similar or stronger immune responses compared to professional antigen-presenting cells.
Antigen cross-presentation or cross-dressing could be more impactful for immune responses than direct mRNA expression in professional antigen-presenting cells.
mRNA expression in hepatocytes is associated with a suppression of the antigen-specific T cell response, partly through the PD1/PDL1 pathway.
Using synthetic microRNA target sites in mRNA vaccines may enhance immune responses by silencing expression in hepatocytes.
In a mouse model with tumor-associated antigen-expressing lymphoma cells, silencing hepatocyte expression improved immune response and reduced tumor burden.

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Proteins encoded by mRNA vaccines can be expressed by a diversity of transfected cell types but how cell-type-specific expression influences immunity is poorly understood. To investigate this, we incorporated synthetic microRNA target sites (miRT) into lipid nanoparticle (LNP)-delivered mRNA vaccines to silence mRNA expression specifically in professional antigen-presenting cells (pAPCs), hepatocytes or myocytes. We found that mRNA expression in pAPCs was dispensable for priming antigen-specific T cells, whereas mRNA expression in myocytes induced similar or stronger immune responses, including for SARS-CoV-2, suggesting that antigen cross-presentation or cross-dressing may be more impactful than direct mRNA expression in pAPCs. In contrast, mRNA expression in hepatocytes suppressed the antigen-specific T cell response, partly through PD1/PDL1. In mice bearing tumor-associated antigen (TAA)-expressing lymphoma cells, miRT-mediated hepatocyte-silenced TAA mRNA vaccine enhanced immune response and reduced tumor burden. Thus, non-pAPC expression shapes immunity to mRNA-encoded protein and inclusion of miRTs can boost or blunt mRNA-LNP immunogenicity.