New Research Challenges Understanding of mRNA Vaccines and Establishes Innovative Way to Make Them More Effective
Preclinical study shows non-immune cells shape mRNA vaccine responses and offers a path to more effective cancer vaccines
A new study by researchers at the Icahn School of Medicine at Mount Sinai overturns a longstanding assumption about how mRNA vaccines generate immunity, revealing that certain non-immune cells help determine vaccine effectiveness.
The study, published in the April 29, 2026 online issue of Nature Biotechnology [https://doi.org/10.1038/s41587-026-03099-z], also introduces a powerful and versatile technology to control the expression of mRNA drugs, which the researchers demonstrate can enhance the effectiveness of mRNA cancer vaccines in preclinical studies of lymphoma.
The findings provide a new framework for designing mRNA vaccines and mRNA therapeutics, with immediate implications for cancer immunotherapy, infectious disease vaccines, and gene-editing treatments.
“This study fundamentally changes how we think mRNA vaccines work,” says Brian D. Brown, PhD, senior author of the study and Director of the Icahn Genomics Institute at the Icahn School of Medicine at Mount Sinai. “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”
Instead, the team found that non-immune cells, particularly muscle cells and liver cells, can play a role in shaping the immune response. Muscle cells can amplify immunity, while liver cells can suppress it. Importantly, the researchers use a novel technology to control which cells express the vaccine, allowing them to enhance or dampen mRNA immunity. This can help to make the vaccines more potent for cancer treatment or, alternatively, provide a way to use mRNA to turn down immune responses to treat autoimmune disease.
Rethinking the biology of mRNA vaccines
mRNA vaccines, best known for their role in combating COVID-19, work by delivering genetic instructions that enable cells to produce a target protein, which in turn triggers an immune response. When the mRNA is injected into the body, both immune and non-immune cells can take up and express the mRNA. Until now, the impact of mRNA expression in non-immune cells has been poorly understood.
To address this, the researchers employed a technology first developed by Dr. Brown to precisely control where mRNA is expressed in the body. By incorporating short sequences known as microRNA target sites into the mRNA, they were able to selectively “turn off” mRNA expression in specific cell types, including dendritic cells, hepatocytes (liver cells), and muscle cells.
Immune cell expression not required for vaccine priming
Using the microRNA target sites, the team made a surprising discovery: mRNA expression in dendritic cells and other immune cells is not required to generate strong T cell responses, including against SARS-CoV-2 antigens.
“This was unexpected,” says Dr. Brown. “It tells us that other cells are producing the vaccine antigen and handing it off to the immune system. That process, called cross-presentation, was known to be key for traditional vaccines. We now know it is also important for mRNA vaccines, and this changes how we think about their design.”
Muscle boosts immunity, liver suppresses it
Another notable and surprising finding from the study was the role of different non-immune cell types in mRNA vaccination. The team found that when mRNA expression was turned off in muscle fibers, the T cell response was reduced. In contrast, when mRNA expression in hepatocytes was turned off, the T cell response was tripled. These results demonstrate that these non-immune cells contribute to mRNA vaccine immunity, which was not known.
“We found that hepatocytes actively dampen the immune response to mRNA vaccines,” says Sophia Siu, an MD/PhD student at the Icahn School of Medicine at Mount Sinai and co-lead author of the study. “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.”
Stronger cancer vaccine responses
The implications were especially pronounced in cancer models. In mice with lymphoma, an mRNA vaccine engineered to avoid hepatocyte expression led to a more than 50 percent reduction in tumor burden. This was because the hepatocyte-silenced vaccine boosted more killer T cells than the traditional mRNA vaccine.
“These results show that we can make mRNA cancer vaccines more effective simply by controlling where the mRNA-encoded antigen is expressed,” says cancer vaccine expert Josh Brody, MD, Director of the Lymphoma Immunotherapy Program at the Mount Sinai Tisch Cancer Center and one of the study authors. “It’s a new lever for improving immunotherapy.”
The study also found that silencing the mRNA in hepatocytes reduced hepatocyte death when the mRNA was used to boost pre-existing T cells, an important finding for therapies involving gene editing or CAR-T cells.
“mRNA vaccines are already very safe,” says Dr. Brody. “What this work shows is that we can make them even safer and more effective by precisely controlling where they act.”
Broad implications beyond vaccines
Beyond infectious disease and cancer, the findings could influence the design of a wide range of mRNA-based therapies, including CRISPR gene editing, in vivo cell reprogramming, and treatments for autoimmune and genetic diseases.
“The ability to tune the immune response up or down is incredibly powerful,” says Dr. Brown. “We now have both a conceptual framework and a practical technology to do that.”
A new design principle for mRNA medicine
While the study was conducted in animal models, the researchers note that the underlying immune mechanisms are conserved and likely to translate to humans.
“mRNA technology is transformative for medicine. We can generate treatments that were not previously possible. Our work provides a new set of design rules for mRNA vaccines and therapeutics,” says Dr. Brown. “As this technology continues to evolve, understanding and controlling where mRNA is expressed will be critical.”
Next, the investigators plan to harness the technology to further improve mRNA treatments for solid organ cancers and to exploit their findings to make mRNA vaccines that can be used to treat autoimmune diseases.
The paper is titled “mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression.”
The study’s authors, as listed in the journal, are Adam Marks, Sophia Siu, Filippo Bianchini, Chunxi Wang, Ashwitha Lakshmi, Matthew Phelan, Andrew Zhu, Chang Moon, Judit Morla-Folch, Abraham Teunissen, Angelo Amabile, Alessia Baccarini, Miriam Merad, Joshua D. Brody, Yizhou Dong, and Brian D. Brown.
The work was supported by NIH grants (R01DK138025, R01CA257195, F30AI194739, T32AI078892) and the Feldman Family Foundation.
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the seven member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City’s large and diverse patient population.
The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master’s degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,700 clinical residents and fellows training throughout the Health System. The Graduate School of Biomedical Sciences offers 13 degree-granting programs, conducts innovative basic and translational research, and trains more than 470 postdoctoral research fellows.
Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 90th percentile of U.S. private medical schools in Sponsored Programs Direct Expenditures per Principal Investigator, according to the Association of American Medical Colleges. More than 6,900 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 47,000 employees working across seven hospitals, more than 400 outpatient practices, more than 600 research and clinical labs, a school of nursing, and leading schools of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time—discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
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