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A leucine derivate-adjuvanted LNP vaccine enhances antitumor immunity through mTOR activation and metabolic reprograming in dendritic cells

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机构： [1]The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Department of Emergency, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, PR China [2]Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, PR China [3]Graduate School of Biomedical Engineering, ARC Centre of Excellence in Nanoscale Biophotonics, Faculty of Engineering, UNSW Sydney, NSW, 2052, Australia [4]School of Biomedical Engineering, University of Technology Sydney, Ultimo, NSW, 2007, Australia [5]State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, PR China

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关键词： LNP cancer vaccine LLOMe Vaccine adjuvant Lysosomal escape mTOR

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Neoantigen-derived peptide vaccines have been emergingly employed to treat tumors, however, their inefficient delivery and antigenicity remain challenging. In this study, for the first time a leucine derivate LLOMe (L-leucyl-l-leucine methyl ester) was repurposed to the adjuvant to reinforce the immune responses of lipid nanoparticle (LNP)-based peptide vaccine. Mechanistically, LLOMe disrupted the lysosomal entrapment of vaccine thus effectively enhanced bioavailability of antigens. Moreover, LLOMe in vaccine was found to stimulate the functional level of APCs via mTOR programed metabolism, while mTOR inhibitor rapamycin could abolish the adjuvating effect of LLOMe. In various animal tumor models receiving prophylactic or therapeutic vaccinations adjuvanted by LLOMe, the effective suppression of tumor growth was achieved through enhanced delivery of antigens and modulation of cellular immune responses. This study demonstrated that LLOMe-induced adjuvanticity significantly enhance the anti-tumor immunity of LNP vaccines, providing a clinically translational and potent adjuvant strategy for developing cancer vaccines.Copyright © 2025 Elsevier Ltd. All rights reserved.

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大类 | 1 区

医学

小类 | 1 区工程：生物医学 1 区材料科学：生物材料

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Q1 ENGINEERING, BIOMEDICAL Q1 MATERIALS SCIENCE, BIOMATERIALS

影响因子： 12.9 最新[2024版] 13.4 最新五年平均 0 出版当年[2025版] 0 出版当年五年平均 12.9 出版前一年[2024版]

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第一作者机构： [1]The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Department of Emergency, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, PR China

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