X‑ray Induced Persistent Type I PhotodynamicTherapy with Enhanced Hypoxia Tolerance and Chemoradiotherapy

The hypoxic tumor microenvironment (TME), inadequate penetration depth of Vis/NIR light, and lack of sustaining reactive oxygen species (ROS) production capability of photosensitizers pose significant obstacles to the widespread clinic applications of photodynamic therapy (PDT). Herein, we developed a “persistent type I X-PDT” platform to simultaneously overcome these three limitations. Such a nanoplatform could generate efficient ROS (^•OH and O₂^•–) under X-ray irradiation in both normoxic and hypoxic environments. The ROS production persists in tumor cells for more than 4 h, even after the X-ray source is removed. Notably, the persistent type I X-PDT does not increase the levels of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in tumor cells both <i>in vitro</i> and <i>in vivo</i>. Moreover, to further enhance the radiotherapy efficacy in hypoxic conditions, a Pt (IV) prodrug was also introduced, which can be reduced to cisplatin selectively in tumor cells, functioning not only as a chemodrug but also as a radiosensitizer.