mRNA vaccines work by delivering genetic instructions into cells, but a new study shows that which cells express the mRNA can alter the resulting immune response. A new study in Nature Biotechnology shows that detargeting mRNA expression away from hepatocytes strengthens T‑cell immunity in preclinical lymphoma models, revealing a new design principle for next‑generation mRNA vaccines and therapeutics.
The work comes from researchers at the Icahn School of Medicine at Mount Sinai, who report that non‑immune cells—including muscle fibers and hepatocytes—play a decisive role in determining mRNA vaccine potency. Their paper, “mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression,” was published today. The findings overturn a long‑held assumption that mRNA vaccines must deliver their payload to dendritic cells to prime strong T‑cell responses.
“This study fundamentally changes how we think mRNA vaccines work,” said senior author Brian D. Brown, PhD, director of the Icahn Genomics Institute. “For years, the field has assumed that getting the mRNA into dendritic cells, the immune cells that activate T cells, was essential. We show that’s not the case. These cells are still important, but mRNA delivery to them is not required.”
To dissect how different cell types influence immunity, the team used a microRNA‑based technology developed in Brown’s lab that allows researchers to “turn off” mRNA expression in specific cell populations. By incorporating short microRNA target sequences into the mRNA, they selectively silenced expression in dendritic cells, hepatocytes, or muscle cells while leaving other tissues unaffected.
The results were striking. Silencing mRNA expression in dendritic cells did not impair T‑cell priming, including for SARS‑CoV‑2 antigens, suggesting that cross‑presentation by other cell types is sufficient to initiate immunity. “This was unexpected,” said Brown. “It tells us that other cells are producing the vaccine antigen and handing it off to the immune system.” In contrast, turning off expression in muscle fibers weakened the immune response, while turning off expression in hepatocytes tripled it.
“We found that hepatocytes actively dampen the immune response to mRNA vaccines,” said Sophia Siu, an MD/PhD student and co‑lead author. “This is notable because hepatocytes can take up a lot of mRNA, particularly when it’s injected intravenously. For vaccines, we discovered that we don’t want expression in hepatocytes. However, for mRNA therapeutics, hepatocyte expression can be beneficial because it may help prevent immunity to the mRNA-encoded protein.”
“In mice bearing tumor-associated antigen (TAA)-expressing lymphoma cells, miRT-mediated hepatocyte-silenced TAA mRNA vaccine enhanced immune response and reduced tumor burden,” wrote the authors. The approach also reduced hepatocyte death when mRNA was used to boost pre‑existing T cells, an important consideration for gene‑editing and CAR T–related applications.
“These results show that we can make mRNA cancer vaccines more effective simply by controlling where the mRNA‑encoded antigen is expressed,” said Joshua D. Brody, MD, director of the Lymphoma Immunotherapy Program at the Mount Sinai Tisch Cancer Center. “It’s a new lever for improving immunotherapy.”
Beyond oncology, the findings could influence the design of mRNA‑based vaccines for infectious diseases and therapeutics for autoimmune and genetic disorders. By tuning expression in specific cell types, researchers can amplify or dampen immune responses as needed.
“mRNA technology is transformative for medicine,” Brown said. “Our work provides a new set of design rules for mRNA vaccines and therapeutics. As this technology continues to evolve, understanding and controlling where mRNA is expressed will be critical.”
