Radiotherapy is a widely used clinical treatment for locoregional cancers, but still faces with radiation resistance arising from abundant glutathione (GSH) and DNA damage repair (DDR). To overcome these self-defensive 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) composing of chemotherapeutic thioguanine as a linker and copper iodide as nodes, is rationally designed for tailored chemoradiotherapy against self-defensive pathways of tumor. Unlike conventional carrier-based systems, aaMOF releases all active components (copper iodide and thioguanine) upon GSH triggered disassembly. Subsequently, much DNA double-stranded break and reactive oxygen species can be generated by iodide promoted X-ray energy deposition and Cu+-catalyzed Fenton reaction. Simultaneously, the released thioguanine incorporates into DNA skeleton, inhibiting the DDR process. As a result, self-defensive pathways of tumor were disrupted by aaMOF driven GSH depletion and DDR inhibition, enabling the tailored chemoradiotherapy. The aaMOF-based radiotherapy exhibits remarkable antitumor efficacy in both cells and xenograft tumor models, fully taking the advantages of all-active MOF components against tumor self-defensive for maximizing therapeutic effects.
