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.