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Transl. Med."],"published-print":{"date-parts":[[2025,12,3]]},"abstract":"<jats:p>\n                    Metabolic dysfunction\u2013associated fatty liver disease (MAFLD), a leading cause of hepatocellular carcinoma (HCC), poses a formidable therapeutic challenge because of the metabolic stress\u2013induced 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\u2013derived 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\n                    <jats:sup>TCPTP<\/jats:sup>\n                    ) 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\n                    <jats:sup>TCPTP<\/jats:sup>\n                    successfully eliminated steatohepatitis, impeded hepatocarcinogenesis, and improved the therapeutic responsiveness of HCC to cancer vaccine and immune checkpoint blockade therapy. Def-LNP@mRNA\n                    <jats:sup>TCPTP<\/jats:sup>\n                    represents a potential therapeutic strategy for MAFLD and MAFLD-related HCC, potentially offering treatment paradigms for immunotherapy for HCC and metabolic liver diseases.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adv2293","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T18:58:11Z","timestamp":1764788291000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":16,"title":["Metabolism-programming mRNA-lipid nanoparticles remodel the immune microenvironment to improve immunotherapy against MAFLD"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6229-2449","authenticated-orcid":true,"given":"Xinyang","family":"Yu","sequence":"first","affiliation":[{"name":"Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2744-5387","authenticated-orcid":true,"given":"Shaolong","family":"Qi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2232-5065","authenticated-orcid":true,"given":"Wanyue","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P. R. China."},{"name":"MOE Joint International Research Laboratory of Pancreatic Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P. R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4113-9687","authenticated-orcid":true,"given":"Meiqi","family":"Cheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangfan","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rujia","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P. R. China."},{"name":"MOE Joint International Research Laboratory of Pancreatic Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P. R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaowei","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P. R. China."},{"name":"MOE Joint International Research Laboratory of Pancreatic Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P. R. 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