癌症研究
免疫系统
免疫疗法
医学
肿瘤微环境
肝细胞癌
癌症免疫疗法
免疫学
STAT蛋白
肝癌
癌症
体内
癌细胞
脂肪肝
药理学
生物
免疫检查点
干扰素
信号转导
脂质代谢
细胞疗法
车站3
重编程
腺病毒科
细胞
遗传增强
肝硬化
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
标识
DOI:10.1126/scitranslmed.adv2293
摘要
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.
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