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In this study, a novel nanobody targeting TM4SF1 is developed, which replaced the conventional single\u2010chain variable fragment (scFv) in the design of CAR\n                    <jats:sup>TM4SF1<\/jats:sup>\n                    \u2010NKT cells. Moreover, CAR\n                    <jats:sup>TM4SF1<\/jats:sup>\n                    \u2010extracellular vesicles (EVs) therapy as an optimized alternative to direct CAR\u2010NKT cell administration is introduced. Compared with conventional CAR\n                    <jats:sup>TM4SF1<\/jats:sup>\n                    engineered cells, CAR\n                    <jats:sup>TM4SF1<\/jats:sup>\n                    \u2010EVs demonstrated superior antitumor efficacy while significantly reducing toxicity. This findings revealed that CAR\n                    <jats:sup>TM4SF1<\/jats:sup>\n                    \u2010EVs selectively targeted TM4SF1\u2010expressing tumor cells in both in vitro and in vivo models. In hepatocellular carcinoma (HCC) mouse models, CAR\n                    <jats:sup>TM4SF1<\/jats:sup>\n                    \u2010EVs induced immunogenic cell death (ICD) and effectively suppressed tumor growth and metastasis. The therapeutic efficacy of CAR\n                    <jats:sup>TM4SF1<\/jats:sup>\n                    \u2010EVs is primarily attributed to their ability to remodel the immunosuppressive tumor microenvironment (TME), notably by enhancing CD8\u207a T cell activity and eliciting robust antitumor immune responses. Furthermore, CAR\n                    <jats:sup>TM4SF1<\/jats:sup>\n                    \u2010EVs synergized with Immune Checkpoint Blockade (ICB) therapy, leading to durable antitumor immune memory. Collectively, these findings establish CAR\n                    <jats:sup>TM4SF1<\/jats:sup>\n                    \u2010EVs therapy as a safe and effective strategy for targeted cancer immunotherapy, underscoring its potential for clinical application.\n                  <\/jats:p>","DOI":"10.1002\/advs.202521623","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T10:22:38Z","timestamp":1768904558000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Engineered CAR\u2010NKT Extracellular Vesicles Suppress Tumor Progression and Enhance Antitumor Immunity"],"prefix":"10.1002","volume":"13","author":[{"given":"Xiaopei","family":"Hao","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery The Affiliated Cancer Hospital of Zhengzhou University &amp; Henan Cancer Hospital Zhengzhou 450008 China"},{"name":"Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation Chinese Academy of Medical Sciences, NHC Key laboratory of Hepatobiliary Cancers Nanjing 210029 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengming","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Department of Biochemistry and Molecular Biology The University of Chicago Chicago IL 60637 USA"},{"name":"Zhongnan Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary &amp; Pancreatic Diseases of Hubei Province Wuhan University Wuhan 430071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanzhao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology The Affiliated Cancer Hospital of Zhengzhou University &amp; Henan Cancer Hospital Zhengzhou 450008 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery The Affiliated Cancer Hospital of Zhengzhou University &amp; Henan Cancer Hospital Zhengzhou 450008 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangjun","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery The Affiliated Cancer Hospital of Zhengzhou University &amp; Henan Cancer Hospital Zhengzhou 450008 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery The Affiliated Cancer Hospital of Zhengzhou University &amp; 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