ABSTRACT Type I photodynamic therapy (PDT) overcomes oxygen (O 2 ) 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 O 2 to form superoxide (O 2 −• ), while the cationic radical oxidized key metabolic cofactor flavin adenine dinucleotide (FADH 2 ) 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 ( 1 O 2 ) generation. Theoretical calculations revealed that AQTPE possessed a markedly reduced singlet‐triplet energy gap (Δ E ST = 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.
Zhang et al. (Sun,) studied this question.