Spatial Confinement of Platinum Nanoclusters in a Photoactive Metal–Organic Framework for Radiotherapy Enhancement and Redox-Mediated Immune Activation

Yuxuan XiongUniversity of Chicago

J LiUniversity of Chicago

Chaoyu WangLudwig Cancer Research

Langston TillmanUniversity of Chicago

Xiaomin JiangLudwig Cancer Research

Alitza L SoifferUniversity of Chicago

R. R. WeichselbaumLudwig Cancer Research

Wei LinWestlake University

Journal of the American Chemical Society·February 6, 2026

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Abstract

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.

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