Spatial Confinement of Platinum Nanoclusters in a Photoactive Metal-Organic Framework for Radiotherapy Enhancement...

Tumor resistance to radiotherapy (RT) and immune checkpoint blockade (ICB) is frequently driven by an immunosuppressive tumor microenvironment, where hypoxia and elevated redox buffering impair both cytotoxic and immune responses. Here, we report a new type of metal-organic framework (MOF)-based radiosensitizer, Pt/Hf-Ir-DBB, that integrates high Z-element-mediated RT enhancement, catalytic redox disruption, and sustained chemotherapeutic delivery into a single multifunctional platform. By confining ultrafine platinum nanoclusters (Pt NCs) within the photoactive Hf-Ir-DBB MOF via photoreduction, this multifunctional system amplifies the hydroxyl radical and singlet oxygen generation under X-ray irradiation. The embedded mixed-valence Pt NCs exhibit potent catalytic activities toward NADH oxidation, H₂O₂ decomposition, and GSH depletion, thereby alleviating hypoxia and disrupting mitochondrial redox homeostasis. Acting as a sustained-release depot, Pt/Hf-Ir-DBB gradually releases Pt²⁺ ions for prolonged chemotherapeutic action. This multimodal strategy reprograms the tumor microenvironment by promoting M1-like macrophage polarization and remodeling the extracellular matrix, ultimately facilitating CD8⁺ T cell activation and infiltration and restoring responsiveness to ICB. In murine colorectal cancer and triple-negative breast cancer models, Pt/Hf-Ir-DBB combined with low-dose X-ray irradiation synergistically enhances both local tumor control and systemic antitumor immunity. These findings establish a rational strategy for overcoming metabolic and immune resistance using MOF-based multifunctional nanoradiosensitizers.