All-component-active metal-organic frameworks for tailored chemoradiotherapy of self-defensive tumors

Radiotherapy is a widely used clinical treatment for locoregional cancers, but it still faces radiation resistance arising from abundant glutathione (GSH) and DNA damage repair (DDR). To overcome these self-defense pathways, various radiosensitizers have often been integrated with pharmaceutical agents, forming hybridized carriers for combination therapy. Herein, an all-component-active metal-organic framework (aaMOF), composed of chemotherapeutic thioguanine as a linker and copper iodide as nodes, is rationally designed for tailored chemoradiotherapy against tumor self-defense pathways. Unlike conventional carrier-based systems, aaMOF releases all active components (copper iodide and thioguanine) upon GSH-triggered disassembly. Subsequently, high levels of DNA double-stranded breaks and reactive oxygen species (ROS) can be generated by iodide-promoted X-ray energy deposition and the Cu⁺-catalyzed Fenton reaction. Simultaneously, the released thioguanine incorporates into the DNA skeleton, inhibiting the DDR process. As a result, tumor self-defense pathways were disrupted by aaMOF-driven GSH depletion and DDR inhibition, enabling tailored chemoradiotherapy. aaMOF-based radiotherapy exhibits remarkable antitumor efficacy in both cells and a xenograft tumor model. This approach fully leverages the benefits of the all-active MOF components to overcome tumor self-defensive mechanisms and maximise therapeutic outcomes.