A study published in Nature Biotechnology has challenged a foundational assumption in mRNA vaccine design, demonstrating that delivery to dendritic cells, long considered essential for generating a strong immune response, is not required for effective T cell priming. Researchers at the Icahn School of Medicine at Mount Sinai found instead that non-immune cells, particularly muscle and liver cells, play a previously unrecognised role in shaping vaccine-induced immunity.
Using microRNA target sequences incorporated into mRNA constructs, the team selectively silenced mRNA expression in specific cell types, including dendritic cells, hepatocytes, and muscle fibres, without affecting other cell types. This allowed them to dissect the contribution of each cell type to the overall immune response.
When mRNA expression was silenced in muscle cells, T cell responses were reduced. When expression in hepatocytes was silenced, T cell responses tripled. The findings indicate that muscle cells amplify immunity, while hepatocytes actively suppress it. This is particularly relevant for intravenous mRNA delivery, where a substantial proportion of mRNA is taken up by liver cells.
In preclinical lymphoma models, an mRNA cancer vaccine engineered to avoid hepatocyte expression produced a greater than 50% reduction in tumour burden compared to a standard mRNA vaccine, attributed to a more robust cytotoxic T cell response. Hepatocyte silencing also reduced liver cell death in the context of T cell-boosting therapies, with implications for the safety of gene editing and CAR-T cell treatments.
The authors note that the immune mechanisms identified are likely conserved in humans and suggest the findings provide new design principles applicable across cancer vaccines, infectious disease immunisation, and mRNA-based therapies for autoimmune and genetic conditions.
Source: Icahn School of Medicine at Mount Sinai. mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression. Nature Biotechnology (2026). DOI: 10.1038/s41587-026-03099-z
Using microRNA target sequences incorporated into mRNA constructs, the team selectively silenced mRNA expression in specific cell types, including dendritic cells, hepatocytes, and muscle fibres, without affecting other cell types. This allowed them to dissect the contribution of each cell type to the overall immune response.
When mRNA expression was silenced in muscle cells, T cell responses were reduced. When expression in hepatocytes was silenced, T cell responses tripled. The findings indicate that muscle cells amplify immunity, while hepatocytes actively suppress it. This is particularly relevant for intravenous mRNA delivery, where a substantial proportion of mRNA is taken up by liver cells.
In preclinical lymphoma models, an mRNA cancer vaccine engineered to avoid hepatocyte expression produced a greater than 50% reduction in tumour burden compared to a standard mRNA vaccine, attributed to a more robust cytotoxic T cell response. Hepatocyte silencing also reduced liver cell death in the context of T cell-boosting therapies, with implications for the safety of gene editing and CAR-T cell treatments.
The authors note that the immune mechanisms identified are likely conserved in humans and suggest the findings provide new design principles applicable across cancer vaccines, infectious disease immunisation, and mRNA-based therapies for autoimmune and genetic conditions.
Source: Icahn School of Medicine at Mount Sinai. mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression. Nature Biotechnology (2026). DOI: 10.1038/s41587-026-03099-z
