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

作者：Xinyang Yu, Shaolong Qi, Wanyue Cao, Meiqi Cheng, Wenjie Zhang, Yangfan Wang, Rujia Zheng, Gaowei Jin, Xiaomin Gao, Meixin Lu, Jiaqi Lei, Kun Peng, Xinhui Su, Qi Zhang, Guocan Yu · 发表于：Science Translational Medicine · 年份：2025 · DOI：10.1126/scitranslmed.adv2293 · 被引用次数：10 · 研究领域：Hepatocellular Carcinoma Treatment and Prognosis、Liver Disease Diagnosis and Treatment、RNA Interference and Gene Delivery

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...