Understanding of mRNA vaccines' mechanism of action is being rewritten and suggest ways to boost effectiveness

Researchers at Icahn School of Medicine have shown that muscle and liver cells influence mRNA vaccine responses, while a novel microRNA-based platform has enabled precise control of antigen expression to improve cancer immunotherapy

A team from the Icahn School of Medicine at Mount Sinai, New York, USA, has challenged a central assumption in vaccinology by demonstrating that non-immune cells play a decisive role in shaping immune responses to messenger ribonucleic acid (mRNA) vaccines. The study has also introduced a versatile platform to regulate where mRNA is expressed in the body, with preclinical data indicating improved performance of mRNA cancer vaccines in lymphoma models.

The findings have established a revised conceptual framework for the design of mRNA vaccines and therapeutics, with implications that extend across cancer immunotherapy, infectious disease prevention and gene-editing strategies.

“This study fundamentally changes how we think mRNA vaccines work,” said Dr. Brian D. Brown, 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 [now] show that is not the case. These cells are still important but mRNA delivery to them is not required,” he said.

mRNA vaccines – which gained prominence through their use during the COVID-19 pandemic – operate by delivering genetic instructions that prompt host cells to synthesise a target antigen which then elicits an immune response. After administration, both immune and non-immune cells can internalise the mRNA construct, yet the functional consequences of expression in non-immune cell populations have remained poorly defined.

To address this gap, the investigators employed a technology developed by Brown and his colleagues to control cellular expression with high specificity. By inserting microRNA target sites into the mRNA sequence, the team has enabled selective silencing of expression in defined cell types, including dendritic cells, hepatocytes and muscle fibres. This approach has allowed direct assessment of how distinct cellular compartments contribute to vaccine-induced immunity.

The study reported an unexpected result. Strong T cell responses, including those directed against COVID-19’s severe acute respiratory syndrome coronavirus 2 antigens, did not require mRNA expression within dendritic cells or other antigen-presenting cells. Instead, the data indicated that antigen production in alternative cell populations, followed by transfer to the immune system through cross-presentation, drives T cell activation.

“This was unexpected,” Brown said.

“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,” he added.

Further experiments have revealed divergent roles for distinct non-immune cell types. When mRNA expression was suppressed in muscle fibres, the T cell response diminished which indicated that these cells amplify immunity. In contrast, suppression of expression in hepatocytes led to a threefold increase in T cell responses, which demonstrates that liver cells exert an inhibitory effect.

“We found that hepatocytes actively dampen the immune response to mRNA vaccines,” said Sophia Siu, a doctoral candidate and medical student, 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,” she said.

The translational potential of these findings has emerged clearly in oncology models. In mouse model lymphoma systems, an mRNA vaccine engineered to avoid hepatocyte expression produced more than a 50 per cent reduction in tumour burden compared with conventional designs. This effect was attributed to an increase in cytotoxic T lymphocyte activation.

“These results show that we can make mRNA cancer vaccines more effective simply by controlling where the mRNA-encoded antigen is expressed,” said Dr. Josh Brody, director of the lymphoma immunotherapy program at the Mount Sinai Tisch Cancer Center and a co-author of the study.

“It’s a novel lever [to be able to pull] for improving immunotherapy,” he said.

The study has also identified safety-relevant effects. Silencing mRNA expression in hepatocytes reduced hepatocyte death in settings where the platform was used to expand pre-existing T cell populations, a result that may prove important for applications in gene editing and chimeric antigen receptor T cell therapy (CAR T).

“mRNA vaccines are already very safe,” said Brody.

“What this work shows is that we can make them even safer and more effective by precisely controlling where they act,” he added.

Beyond oncology and infectious disease, the ability to modulate immune activation has implications for a broad range of emerging therapeutic modalities, including clustered regularly interspaced short palindromic repeats (CRISPR) mediated gene editing, in vivo cellular reprogramming and interventions for autoimmune and inherited disorders. The capacity to either amplify or suppress immune responses through spatial control of antigen expression represents a significant shift in design strategy.

“The ability to tune the immune response up or down is incredibly powerful. We now have both a conceptual framework and a practical technology to do that,” said Brown.

Although the work has only been conducted in animal models, the investigators have indicated that the underlying immunological mechanisms are conserved which suggests that translation to human systems is plausible.

“mRNA technology is transformative for medicine. We can generate treatments that were not previously possible. Our work provides a novel set of design rules for mRNA vaccines and therapeutics,” said Brown.

“As this technology continues to evolve, understanding and controlling where mRNA is expressed will be critical,” he concluded.

The research team has stated that it intends to extend the approach to solid organ malignancies and to explore applications in autoimmune disease, where suppression of immune activation may offer therapeutic benefit.

For further reading please visit: 10.1038/s41587-026-03099-z