Single\nMolecule for Trifecta PDT: Tailor-Made Three-Organelle-Targeting\nType I Photosensitizer for Cancer Cell-Selective Photodynamic Therapy\nunder Hypoxia

Cancer cell-selective multiorganelle-targeting type I\nphotosensitizers\n(PSs) may greatly enhance the treatment efficiency of photodynamic\ntherapy (PDT) and revolutionize cancer therapy. However, the related\nsystematic design strategies remain vague. Herein, we developed a\nseries of three-organelle-targeting PSs with varied N-containing substituents,\nwhich localized in the plasma membrane, mitochondria, and nucleus\nof cancer cells. These molecules exhibited diverse photosensitizing\ncapabilities, ranging from non-photosensitivity to pure type I or\nII photosensitization or a mix of type I/II photosensitization. We\ninvestigated and discussed the structure–function relationship\namong these molecules. Notably, ACR-DME, as a type I PS, can selectively\nbind to cancer cells over noncancer cells, which demonstrated impressive\nPDT efficacy to cancer cells under hypoxic conditions and effectively\ncurbed the proliferation of 4T1 tumors <i>in vivo</i>. Our\nfindings contribute valuable insights for the design of effective\nPSs for trifecta PDT under hypoxic conditions, propelling advancements\nin cancer treatment strategies.