The development of photosensitizers that function effectively in hypoxic environments and enable deep-tissue treatment remains a significant challenge in photodynamic therapy (PDT). Here, we report two novel Ir(III) complexes functionalized with fluorescein designed as efficient Type I photosensitizers for both light-driven PDT and X-ray-induced PDT (X-PDT). By populating the triplet state of the fluorescein ligands, these complexes facilitate the generation of reactive oxygen species (ROS) through electron transfer, producing superoxide anion radicals (O2•-) and hydroxyl radicals (•OH) under irradiation. The complexes exhibit pronounced phototoxicity against cancer cells, particularly under hypoxic conditions, where oxygen-dependent Type II photosensitizers are less effective. Remarkably, these complexes also demonstrate direct X-ray activation, offering a solution for deep-tissue cancer treatment. The lead complex, PS1, outperforms existing systems by efficiently generating both singlet oxygen O2(1Δg) and free radicals, enabling synergistic Type I and II PDT effects. This work represents a major advancement in the design of oxygen-independent PDT agents by using fluorescein's triplet state, with potential applications in deep-tissue and hypoxic tumor environments.

Department of Biochemistry and Microbiology University of Chemistry and Technology Technická 5 166 28 Prague Czech Republic

Department of Chemistry Hong Kong Baptist University Kowloon Tong Hong Kong SAR 999077 China

Department of Chemistry Southern University of Science and Technology 1088 Xueyuan Boulevard Shenzhen 518055 China

Division of Life Science The Hong Kong University of Science and Technology Hong Kong SAR 999077 China

Guangdong Key Laboratory of Nanomedicine Shenzhen Engineering Laboratory of Nanomedicine and Nanoformulations CAS Key Laboratory for Health Informatics Shenzhen Institutes of Advanced Technology Chinese Academy of Sciences Shenzhen 518055 China

Institute of Inorganic Chemistry of the Czech Academy of Sciences Řež 1001 250 68 Husinec Řež Czech Republic

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