Target Reprogramming Lysosomes of CD8+T Cells by a Mineralized Metal-Organic Framework for Cancer Immunotherapy
Target Reprogramming Lysosomes of CD8+T Cells by a Mineralized Metal-Organic Framework for Cancer Immunotherapy
复制标题
通过矿化金属有机框架对 CD8 T 细胞溶酶体进行靶向重编程用于癌症免疫治疗
DOI：
10.1002/adma.202100616
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发表时间：
2021-03-24
影响因子：
29.4
通讯作者：
Zhang, Yufeng
中科院分区：
文献类型：
--
作者：
Zhao, Qin;Gong, Zijian;Zhang, Yufeng
T细胞免疫治疗在实体瘤中面临重大挑战，主要是由于T细胞的低活化和治疗蛋白的合成-释放减少，包括溶酶体中存在的穿孔蛋白和颗粒酶B。在本研究中，通过矿化金属有机框架（MOF）与溶酶体靶向适配体（cd63 -适配体）偶联的方式，开发了一种溶酶体靶向纳米颗粒（LYS-NP），以增强T细胞的抗肿瘤作用。由Zn2+和二甲基咪唑合成的MOF具有良好的蛋白包封性和酸敏感性，是理想的溶酶体传递载体。利用碳酸钙（CaCO3）诱导MOF矿化，提高复合材料包封治疗性蛋白的稳定性，并为钙离子提供协同作用。在矿化之前，穿孔蛋白和颗粒酶B-T细胞（肿瘤所需的治疗蛋白）预先装载了MOF。此外，在对溶酶体进行重编程之前，用加工过的肿瘤特异性抗原对T细胞进行预处理，以激活或产生记忆，促进T细胞受体（TCR）释放治疗蛋白。利用LYS-NPs重组的T细胞，证实了乳腺癌控制的显著增强。
T cell immunotherapy holds significant challenges in solid tumors, mainly due to the T cells' low activation and the decreased synthesis-release of therapeutic proteins, including perforin and granzyme B, which are present in lysosomes. In this study, a lysosome-targeting nanoparticle (LYS-NP) is developed by way of a mineralized metal-organic framework (MOF) coupled with a lysosome-targeting aptamer (CD63-aptamer) to enhance the antitumor effect of T cells. The MOF synthesized from Zn2+ and dimethylimidazole has good protein encapsulation and acid sensitivity, and is thus an ideal lysosomal delivery vector. Calcium carbonate (CaCO3) is used to induce MOF mineralization, improve the composite material's stability in encapsulating therapeutic protein, and provide calcium ions with synergistic effects. Before mineralization, perforin and granzyme B-T cell-needed therapeutic proteins for tumors-are preloaded with the MOF. Moreover, T cells are pretreated with processed tumor-specific antigens to activate or produce memory before reprogramming the lysosomes, facilitating the T cell receptor (TCR) for release of the therapeutic proteins. Using T cells recombined by LYS-NPs, a significant enhancement of breast cancer control is confirmed.