Cao Yufei, Zheng Moujiang, Zhou Qinghao, Dong Yansong, Hou Yuzhu, Ge Zhishen
School of Chemistry, State Key Laboratory of Fluorine & Nitrogen Chemicals, Institute of New Concept Sensors and Molecular Materials (INCSMM), Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Key Laboratory of Sustainable Polymer Materials, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
ACS Appl Mater Interfaces. 2025 Aug 6;17(31):44263-44274. doi: 10.1021/acsami.5c11614. Epub 2025 Jul 27.
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.
放疗（RT）的治疗效果受到肿瘤内活性氧（ROS）生成不足和肿瘤固有放射抗性的显著限制。为了克服这些局限性，我们开发了一种基于聚合物金属有机框架（PMOF）的新型纳米平台，该平台独特地将强效放射增敏与X射线触发的、时空同步释放两种治疗性气体——一氧化碳（CO）和硫化氢（HS）相结合。这个名为SHF@PMOF的平台是通过使用铪（Hf）-氧簇、卟啉连接体（TCPP）和含1,4-苯二甲酸的嵌段共聚物来构建的，形成了能够封装双气体供体硫代-3-羟基黄酮（SHF）的高度多孔结构。至关重要的是，SHF@PMOF作为一种高效的放射增敏剂，在X射线照射下能显著促进ROS的生成。同时，相同的X射线刺激触发了PMOF基质中负载的SHF供体对CO和HS的可控共释放。这种强化的ROS介导放疗与协同的CO/HS气体治疗的创新组合，即使在低辐射剂量下也能显著提高抗癌效果。机制研究表明，双气体释放特异性地诱导线粒体功能障碍，其特征是ATP生成受损、钙缓冲破坏和NADH活性受抑制，这些共同导致放射敏感性增强和有效的肿瘤细胞杀伤。体外和体内研究都确凿地证明了SHF@PMOF加X射线照射的卓越性能，通过这种综合的放疗/气体治疗方法实现了高效的癌症治疗。这项工作开创了使用PMOF纳米载体共递送双气体供体和放射增敏成分的先河，提出了一种通过协同增强ROS和气体敏化放射反应来放大放疗效果的开创性策略。
