X-ray-Triggered Prodrug Activation in a Nanoscale Metal-Organic Framework for Spatially Confined Chemoradiotherapy.

Chemoradiotherapy (CRT) is a cornerstone treatment for many solid tumors, but its therapeutic efficacy is frequently limited by poor tumor selectivity of chemotherapeutic agents. Prodrug strategies responsive to endogenous tumor cues partially address this challenge, yet their intrinsic spatial and temporal heterogeneity constrain precision and reliability. Here we report a mixed-ligand nanoscale metal-organic framework (MOF), P-DTC/Hf12-Ir-Cu, that directly couples X-ray irradiation with spatially confined prodrug activation to enable synchronized chemoradiotherapy. The MOF integrates an {Ir(DBB)(ppy)2}+ photosensitizer and a (DBB)CuCl2 precursor (DBB = 4,4'-di(4-benzoato)-2,2'-bipyridine; ppy = cyclometalated 2-phenylpyridine), serving simultaneously as a radioenhancer and a confined reaction environment for a pyridinium-masked dithiocarbamate prodrug. Upon X-ray irradiation, radiolytically generated electrons within the framework induce reductive prodrug activation, liberating diethyldithiocarbamate, which rapidly sequesters proximal Cu ions from nearby (DBB)CuCl2 linkers to form the highly cytotoxic Cu(DTC)2 complex while concurrently amplifying reactive oxygen species generation. As a result of spatial confinement, the MOF enhances Cu(DTC)2 generation by more than 28-fold compared with a molecular control. Cellular studies reveal pronounced mitochondrial copper accumulation and cuproptosis-associated cell death. In vivo biodistribution studies showed that P-DTC/Hf12-Ir-Cu prolonged intratumoral retention and limited systemic exposure. Consequently, P-DTC/Hf12-Ir-Cu combined with X-ray irradiation achieves potent tumor growth inhibition in vivo under clinically similar fractionated radiation doses with minimal systemic toxicity. This work establishes a general strategy for utilizing X-ray energy for spatially and temporally controlled CRT with nanoscale MOFs.