mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression
Nature Biotechnology, 2026
Marks A., Siu S., Bianchini F., Wang C., Lakshmi A., Phelan M., Zhu A., Moon C., Morla-Folch J., Teunissen A., Amabile A., Baccarini A., Merad M., Brody J., Dong Y., Brown B.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Immunological & Inflammatory Diseases | Pathophysiology | Mouse Cell Culture Supernatant |  Olink Target 96 Mouse |
Abstract
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.