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.