Target Reprogramming Lysosomes of CD8+ T Cells by a Mineralized Metal-Organic Framework for Cancer Immunotherapy.

Zhao, Qin; Gong, Zijian; Li, Zhihao; Wang, Jinyang; Zhang, Jinglun; Zhao, Zifan; Zhang, Peng; Zheng, Shihang; Miron, Richard J.; Yuan, Quan; Zhang, Yufeng (2021). Target Reprogramming Lysosomes of CD8+ T Cells by a Mineralized Metal-Organic Framework for Cancer Immunotherapy. Advanced materials, 33(17), e2100616. Wiley-VCH 10.1002/adma.202100616

Text Advanced_Materials_-_2021_-_Zhao_-_Target_Reprogramming_Lysosomes_of_CD8_T_Cells_by_a_Mineralized_Metal_Organic_Framework.pdf - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (11MB)

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.

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