Metabolism-programming mRNA-lipid nanoparticles remodel the immune microenvironment to improve immunotherapy against...

Metabolic dysfunction-associated fatty liver disease (MAFLD), a leading cause of hepatocellular carcinoma (HCC), poses a formidable therapeutic challenge because of the metabolic stress-induced aberrant immune microenvironment. However, no effective pharmacological therapies for the liver microenvironment remodeling in MAFLD are now available. Here, we developed a lipid nanoparticle (Def-LNP) that incorporates vitamin E-derived phosphatidylcholine (VEPC). Def-LNP effectively ameliorated the hepatic oxidative microenvironment to achieve sustained localized expression of target mRNA in hepatocytes in preclinical models, outperforming a commercially used LNP formulation. In vivo delivery efficiency, stability, and biosafety of Def-LNP were validated in various mammalian models, including mice, pigs, and nonhuman primates. Using clinical samples, we identified a pronounced correlation between T cell protein tyrosine phosphatase (TCPTP) and MAFLD pathogenesis. The administration of Def-LNP loaded with TCPTP-encoding mRNA (Def-LNP@mRNA^TCPTP) suppressed signal transducer and activator of transcription signaling in the hepatocytes of MAFLD mice, leading to hepatic metabolic reprogramming and immunological reconfiguration, a characteristic that is prominently lacking in conventional mRNA-based protein replacement therapy. In preclinical models, the administration of Def-LNP@mRNA^TCPTP successfully eliminated steatohepatitis, impeded hepatocarcinogenesis, and improved the therapeutic responsiveness of HCC to cancer vaccine and immune checkpoint blockade therapy. Def-LNP@mRNA^TCPTP represents a potential therapeutic strategy for MAFLD and MAFLD-related HCC, potentially offering treatment paradigms for immunotherapy for HCC and metabolic liver diseases.