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　in　vitro　and　in　vivo.　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.　©　2025　American　Chemical　Society.