Anthraquinone-Based Electron Reservoir-Pump Photosensitizer Generating Radical Ion Pairs for Metabolism-Targeted Photodynamic Therapy.

Type I photodynamic therapy (PDT) overcomes oxygen (O2) dependence of type II PDT, but developing hypoxia-efficient electron-transfer photosensitizers remains challenging. Herein, we proposed an anthraquinone (AQ)-based single-component "electron reservoir-pump" strategy to enhance the electron transfer ability of type I photosensitizers. In this molecular design, the AQ scaffold functioned as an intrinsic electron reservoir, while the electron-rich tetraphenylethylene (TPE) served as an electron pump that actively donated electrons. The synergistic reservoir-pump interaction enabled the photosensitizer AQTPE to undergo photo-disproportionation and generate radical ion pairs: the anionic radical efficiently reduced O2 to form superoxide (O2 -•), while the cationic radical oxidized key metabolic cofactor flavin adenine dinucleotide (FADH2) to disrupt redox homeostasis and suppress fatty acid synthase (FASN)-mediated metabolism. In contrast, control photosensitizers AQCN and AQNI bearing electron-withdrawing substituents maintained singlet oxygen (1O2) generation. Theoretical calculations revealed that AQTPE possessed a markedly reduced singlet-triplet energy gap (ΔEST = 0.01 eV) and enhanced spin-orbit coupling (7.538 cm-1), facilitating intersystem crossing. Notably, AQTPE nanoparticles exhibited potent type I photodynamic activity and robust tumor suppression even under hypoxic conditions. This study establishes a molecular electronegativity-modulation framework for integrating electron reservoir-pump systems within single-component photosensitizers, offering a general design principle for next-generation metabolism-targeted and hypoxia-tolerant photosensitizers.