Target Reprogramming Lysosomes of CD8+ T Cells by a Mineralized Metal–Organic Framework for Cancer Immunotherapy. Issue 17 (24th March 2021) - Zhao, Qin
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 Zn 2+ 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. Abstract : Lysosome‐targeted drug‐loaded nanoparticles (LYS‐NPs) composed of CD63‐aptamers coupled with mineralized metal–organic frameworks are developed. Using the degradation of the LYS‐NPs in lysosomes, therapeutic proteins and Ca 2+ are stored in the lysosomes of T cells. Next, they are released when the T cell receptor (TCR) of the T cells binds to tumor cells. These elements possess a powerful ability for cancer immunotherapy.