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

Abstract

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.

• Authors: Qin Zhao, Zijian Gong, Zhihao Li, Jinyang Wang, Jinglun Zhang, Zifan Zhao, Peng Zhang, Shihang Zheng, Richard J Miron, Quan Yuan, Yufeng Zhang
• Journal: Advanced materials (Deerfield Beach, Fla.) (Adv Mater) Vol. 33 Issue 17 Pg. e2100616 (Apr 2021) ISSN: 1521-4095 [Electronic] Germany
• PMID: 33760313 (Publication Type: Journal Article)
• Copyright: © 2021 Wiley-VCH GmbH.

Chemical References

• Metal-Organic Frameworks
• Minerals
• Granzymes

Topics

• Animals
• CD8-Positive T-Lymphocytes (cytology)
• Cell Line, Tumor
• Granzymes (metabolism)
• Humans
• Immunotherapy
• Lysosomes
• Metal-Organic Frameworks
• Minerals (metabolism)
• Nanoparticles