mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression
Nature Biotechnology. Published online April 29, 2026. DOI 10.1038/s41587-026-03099-z.
How to cite
AMA
Marks A, Siu S, Bianchini F, Wang C, Lakshmi A, Phelan M, et al. mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression. Nat Biotechnol. Published online April 29, 2026. doi:10.1038/s41587-026-03099-zAPA
Marks, A., Siu, S., Bianchini, F., Wang, C., Lakshmi, A., Phelan, M., et al. (2026). mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression. Nature Biotechnology. Advance online publication. https://doi.org/10.1038/s41587-026-03099-zBibTeX
@article{marks2026mrna,
title = {mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression},
author = {Marks, A. and Siu, S. and Bianchini, F. and Wang, C. and Lakshmi, A. and Phelan, M. and others},
journal = {Nature Biotechnology},
year = {2026},
doi = {10.1038/s41587-026-03099-z},
note = {Advance online publication}
}An mRNA vaccine makes its protein inside whatever cells take up the delivery particle: immune cells, liver cells or muscle. Whether the identity of the producing cell changes the immune response has been hard to test, because you cannot easily switch it off in one cell type while leaving it on in the rest.
This team built that switch. They added short microRNA target sequences to the vaccine mRNA to silence it in one cell type at a time: antigen-presenting cells, hepatocytes or muscle fibers. Silencing the mRNA in antigen-presenting cells did not stop T cell priming, and for a SARS-CoV-2 Spike vaccine it changed nothing. Silencing it in hepatocytes instead raised the antigen-specific T cell response; the suppression it removed ran partly through PD1/PDL1.
In mice with lymphoma, a vaccine engineered to skip hepatocytes drove a stronger response and shrank tumors.
Key findings
- Silencing the vaccine mRNA in hepatocytes roughly tripled the antigen-specific CD8 T cell response. A miR-122 target site raised antigen-specific cells to about 28% of CD8 T cells, from about 10% with the unmodified mRNA, at the same dose and schedule.
- In a lymphoma model, detargeting the tumor antigen from hepatocytes lowered tumor volume by more than 50%. The same vaccine doubled antigen-specific CD8 T cells in the spleen and left tumor-infiltrating T cells less exhausted, with lower PD1 and TIM3.
- Antigen made inside dendritic cells was not required to prime the response. Silencing the vaccine mRNA in antigen-presenting cells still induced antigen-specific CD8 T cells, about 5% of the total versus about 10% with the unmodified mRNA, and changed nothing for a SARS-CoV-2 Spike vaccine; silencing it in muscle fibers instead cut Spike-specific T cells by about 30%.
CyteFinder II HT in the methods
“Slides were automatically imaged on the RareCyte Cytefinder II HT using the following channels: ultraviolet, Cy3, Cy5 and Cy7. Imaging was performed with the following parameters: binning, 1 × 1; objective, ×20; numerical aperture, 0.75; resolution, 0.325 μm per pixel. Image exposures were optimized for each channel to avoid signal saturation but kept constant across samples.”
— Marks et al., Nature Biotechnology (2026), Methods, “Cyclic immunofluorescence”
Why it matters for CyteFinder II HT users
If you are considering the CyteFinder II HT for a tissue study, look at the job it did here. The paper's argument turns on knowing which cells make the vaccine's protein and which immune cells arrive to meet them — questions you can only answer by looking at intact tissue, cell by cell, in more than one color. The authors stained FFPE liver sections across cyclic rounds and scanned them automatically on the CyteFinder II HT in four channels, reading out MHC-I, CD8 T cells and macrophages in the same section. That let them count around 1,100 CD8 T cells per square millimeter in inflamed liver and watch that infiltration fall once hepatocyte expression was silenced. Two things carry over to your own workflow. Automated whole-slide capture means every section is scanned the same way, with exposures held constant, so counts stay comparable across samples and conditions. And multichannel cyclic imaging lets you place antigen and immune markers on one piece of tissue, rather than reading their relationship off separate stains.
