Mount Sinai researchers reported that detargeting mRNA expression away from hepatocytes can strengthen T-cell immunity in preclinical lymphoma models. Published in Nature Biotechnology, the work frames a new design principle for mRNA therapeutics by showing immunity can improve when antigen production in the liver is reduced. The team used microRNA-based tools to silence mRNA expression in specific cell populations, including dendritic cells, hepatocytes, and muscle fibers. They found dendritic-cell targeting was not required for T-cell priming, while hepatocyte expression dampened vaccine immunity. The findings suggest that cell-type-specific biodistribution can be engineered to tune immunogenicity rather than assuming delivery to dendritic cells is the sole critical determinant.