Ha Eun Shin, Jun-Hyeok Han, Joo Dong Park, Minji Park, Jieun Han, Min-Ho Kang, Jung Seung Lee, Chun Gwon Park, Juwon Park, Hyun-Young Kim, Duck Cho, Wooram Park
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引用次数: 0
摘要
自然杀伤(NK)细胞在先天性免疫反应中至关重要,在癌症免疫疗法中大有可为,但在激活和靶向基因递送方面面临挑战。本研究引入了含有 1,2-二油酰-3-三甲基铵丙烷(DOTAP)的双功能脂质纳米颗粒(DLNPs),旨在通过促进激活和高效 CAR mRNA 递送来增强嵌合抗原受体修饰的 NK(CAR-NK)细胞的抗肿瘤功效。DLNPs 是通过对 FDA 批准的 LNP 组合物进行功能化而制成的,具有出色的 mRNA 包封性和胶体稳定性。使用 DLNPs 的 NK 细胞通过细胞外信号调节激酶/丝裂原活化蛋白激酶通路调节和线粒体动力学变化,显示出对癌细胞的更强细胞毒性。DLNPs 主要通过凝集素介导的内吞作用进入 NK 细胞,促进了 mRNA 的传递,克服了 NK 细胞对遗传操作的抵抗力。以肝细胞癌中普遍存在的 glypican-3 为靶标的 CAR-NK 细胞在正位小鼠模型中显示出显著的治疗效果。这些发现强调了DLNPs在增强CAR-NK细胞治疗实体瘤方面的潜力,标志着基于NK细胞的癌症免疫疗法取得了重大进展,为NK细胞相关疾病的干预开辟了广阔的前景。
Enhancing CAR-NK Cells Against Solid Tumors Through Chemical and Genetic Fortification with DOTAP-Functionalized Lipid Nanoparticles
Natural killer (NK) cells are crucial in the innate immune response and show promise in cancer immunotherapy, but face challenges in activation and targeted gene delivery. In this study, bifunctional lipid nanoparticles (DLNPs) containing 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), designed to bolster the antitumor efficacy of chimeric antigen receptor-modified NK (CAR-NK) cells by facilitating activation and efficient CAR mRNA delivery are introduced. The DLNPs, created by functionalizing FDA-approved LNP compositions, exhibit excellent mRNA encapsulation and colloidal stability. NK cells primed with DLNPs show increased cytotoxicity against cancer cells via extracellular signal-regulated kinase/Mitogen-Activated Protein Kinase pathway modulation and mitochondrial dynamics changes. The DLNPs enter NK cells predominantly through clathrin-mediated endocytosis, boosting mRNA delivery and overcoming NK cells' resistance to genetic manipulation. CAR-NK cells targeting glypican-3, prevalent in hepatocellular carcinoma, show significant therapeutic effects in an orthotopic mouse model. These findings underscore the potential of DLNPs in enhancing CAR-NK cell therapy for solid tumors, marking a significant stride in NK cell-based cancer immunotherapy and broadening prospects for NK cell-related disease interventions.
期刊介绍:
Firmly established as a top-tier materials science journal, Advanced Functional Materials reports breakthrough research in all aspects of materials science, including nanotechnology, chemistry, physics, and biology every week.
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