Longevity & AgingEngineered mRNA nanoparticles reprogram fatty liver and boost liver cancer immunotherapy in animal models
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a leading driver of liver cancer, and no drugs currently remodel the stressed, immune-disrupted liver environment it creates. Researchers built a lipid nanoparticle called Def-LNP that includes a vitamin E-derived phosphatidylcholine to counter oxidative stress in the fatty liver, enabling longer-lasting mRNA expression in hepatocytes than a commercially used formulation. They loaded it with mRNA encoding TCPTP, a phosphatase linked to MAFLD in clinical samples. In mouse models, this treatment dampened STAT signaling, reprogrammed liver metabolism and immune cells, eliminated steatohepatitis, slowed tumor development, and improved responses to a cancer vaccine and immune checkpoint blockade. Delivery and safety were also tested in pigs and nonhuman primates. The findings are preclinical, but they suggest a possible strategy for metabolic liver disease and related liver cancer.
