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Chimeric Antigen Receptor-Engineered Cell Membrane-Coated Nanoparticles Promote Dual-Targeted mRNA-Based Cancer Gene Therapy

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机构: [1]Sichuan Univ, West China Hosp, Canc Ctr, Dept Biotherapy, Chengdu 610041, Peoples R China [2]Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China [3]Univ Elect Sci & Technol China, Personalized Drug Therapy Key Lab Sichuan Prov Sic, Sch Med, Dept Pharm, Chengdu 610072, Peoples R China [4]Kunming Univ Sci & Technol, Peoples Hosp Yunnan Prov 1, Affiliated Hosp, Dept Pharm, Kunming 650032, Peoples R China
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关键词: mRNA delivery cell membrane tumor-targeteddelivery chimeric antigen receptor-T-cell therapy immunogenic cell death

摘要:
Gene therapy using mRNA has facilitated progress in cancer therapy. However, its application is hindered by a limited tumor-targeted delivery approach, leading to off-target effects and safety concerns. Chimeric antigen receptor (CAR) molecules enable T cells to recognize specific antigens in a major histocompatibility complex-unrestricted manner. CAR approaches provide an "off-the-shelf" solution for introducing additional targeting functionality to a cell membrane. Cancer cell membrane-coated nanoparticles with homotypic tumor-targeted properties provide a readily accessible platform for gene engineering and membrane extraction. Herein, we demonstrate a CAR-inspired cancer cell membrane-coated platform for delivering an mRNA formulation through a dual tumor-targeted mechanism. The simplified human epidermal growth factor receptor 2 (HER2)-specific CAR molecule (comprising an extracellular HER2-binding domain, a hinge, and a transmembrane domain) was engineered on the cell membrane of cancer cells to establish CAR-CT26 cells. The extracted CAR-CT26 membrane (CARM) was subsequently coated onto the lipid nanoparticle (LNP)-mRNA surface to form a CARM@LNP-mRNA complex. In vitro, the CARM-coated nanoparticles exhibited enhanced mRNA transfection efficiency toward CT26 cells overexpressing target HER2 antigens. Systemic administration of the CARM@LNP-mRNA formulation resulted in stronger tumor-targeting ability and tumor suppression in HER2+ CT26 subcutaneous tumors and peritoneal cavity metastasis models than that observed with the CT26 cell membrane-coated version. Our data suggest that CARM@LNP is a feasible choice for mRNA-based gene therapy. These results provide evidence for the systemic administration of CARM@LNP-mRNA as a promising tumor-targeted therapeutic strategy.

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大类 | 1 区 材料科学
小类 | 1 区 化学:综合 1 区 材料科学:综合 1 区 纳米科技
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Q1 CHEMISTRY, MULTIDISCIPLINARY Q1 CHEMISTRY, PHYSICAL Q1 MATERIALS SCIENCE, MULTIDISCIPLINARY Q1 NANOSCIENCE & NANOTECHNOLOGY

影响因子: 最新[2023版] 最新五年平均 出版当年[2024版] 出版当年五年平均 出版前一年[2023版]

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第一作者机构: [1]Sichuan Univ, West China Hosp, Canc Ctr, Dept Biotherapy, Chengdu 610041, Peoples R China [2]Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China [4]Kunming Univ Sci & Technol, Peoples Hosp Yunnan Prov 1, Affiliated Hosp, Dept Pharm, Kunming 650032, Peoples R China
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通讯机构: [1]Sichuan Univ, West China Hosp, Canc Ctr, Dept Biotherapy, Chengdu 610041, Peoples R China [2]Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
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