PolyMOF Radiosensitizers as Nanocarriers with X-Ray-Triggered Dual-Gas Release for Enhanced Radiotherapy.

The therapeutic efficacy of radiotherapy (RT) is significantly constrained by insufficient intratumoral reactive oxygen species (ROS) generation and the inherent tumor radioresistance. To overcome these limitations, we develop a novel nanoplatform based on polymeric metal-organic frameworks (PMOFs) that uniquely integrates potent radiosensitization with X-ray-triggered, spatiotemporally synchronized release of two therapeutic gases, carbon monoxide (CO), and hydrogen sulfide (HS). This platform, termed as SHF@PMOF, is fabricated by using hafnium (Hf)-oxo clusters, porphyrin linkers (TCPP), and 1, 4-bezenedicarboxylic acid-bearing block copolymers to form highly porous structures capable of encapsulating the dual-gas donor thio-3-hydroxyflavone (SHF). Crucially, SHF@PMOF acts as a highly efficient radiosensitizer, markedly boosting the ROS generation under X-ray irradiation. Simultaneously, the same X-ray stimulus triggers the controlled corelease of CO and HS from the loaded SHF donor within the PMOF matrix. This innovative combination of intensified ROS-mediated radiotherapy and synergistic CO/HS gas therapy leads to dramatically enhanced anticancer efficacy, even at low radiation doses. Mechanistic studies reveal that the dual-gas release specifically induces mitochondrial dysfunction, characterized by impaired ATP production, disrupted Ca buffering, and inhibited NADH activity, which collectively contribute to heightened radiosensitivity and potent tumor cell killing. Both in vitro and in vivo studies conclusively demonstrate the superior performance of SHF@PMOF plus X-ray irradiation, achieving highly efficient cancer treatment through this integrated RT/gas therapy approach. This work pioneers the use of PMOF nanocarriers for codelivering a dual-gas donor and radiosensitizing components, presenting a groundbreaking strategy to amplify RT efficacy via synergistic ROS enhancement and gas-sensitized radioresponse.