Reshaping tumor immune microenvironment and modulating T cell function based on hierarchical nanotherapeutics for synergistically inhibiting osteosarcoma.

T-cell-based immunotherapy shows significant promise for treating osteosarcoma. However, its effectiveness is often limited by the immunosuppressive tumor environment and weakened T-cell activity. In this study, we present a tumor-targeting strategy that aims to reshape the tumor microenvironment and modulate T-cell function using a hierarchical metal-organic framework (MOF). The MOF is armed with PD-L1 antibody (anti-PD-L1) and loaded with C-C motif chemokine ligand 19 (CCL19) and oxaliplatin in separate layers, which enhances the therapeutic efficiency for osteosarcoma. The intricate hierarchical MOFs employed in this research provide a programmable action schedule for the loaded drugs, enabling spatiotemporal control over their release and action. The anti-PD-L1 on the surface of nanoparticles specifically binds to PD-L1 on tumor cells, reinforcing the targeting and recognition capabilities of the materials. Additionally, this targeted approach serves as an immune checkpoint inhibitors therapy, blocking the binding of PD-1 and PD-L1 between T cells and tumor cells. This prevents T-cell exhaustion, thereby restoring their killing ability. Moreover, the initial release of CCL19 from the nanoparticles recruits more T cells into the tumor microenvironment, augmenting the immunotherapy effect. As a result, when oxaliplatin is pH-responsively released from the nanoparticles upon being absorbed by osteosarcoma cells, it exhibits maximum killing ability against the cancer cells.