ABSTRACT Hypoxia continues to pose a significant challenge in photodynamic therapy (PDT) due to the reliance of conventional photosensitizers on oxygen‐dependent mechanisms, which markedly diminishes their efficacy in hypoxic tumor regions. Current improving strategies are often hindered by reduced catalytic efficiency or intricate synthetic processes, highlighting the pressing need for innovative molecular designs. In this study, for the first time, we introduce a self‐adapting function, mitochondria‐targeted photosensitizer TPP‐Cy that employs a novel singlet exciton‐driven electron transport chain (ETC) breakdown mechanism (named Type‐sETC) to achieve oxygen‐independent PDT. Specifically speaking, TPP‐Cy proficiently generates free radical species under normoxia conditions, while directly photocatalyzing critical mitochondrial biomolecules such as NADH and Cyt c in hypoxic, better than most previously reported metal catalysts. Additionally, even under hypoxia conditions, TPP‐Cy ’s photoredox catalysis significantly disrupts ETC, leading to a severe energetic crisis that compromises cellular viability. Importantly, this photon‐driven cell death occurs through immunogenic pyroptosis, thus possessing the potential for antitumor immunotherapy. Mechanistically, TPP‐Cy breaks the traditional triplet sensitization paradigm, achieving efficient electron transfer with biological substrates through singlet exciton dissociation mechanism. This approach minimizes energy loss during intersystem crossing and broadens the range of catalytic substrates, thereby establishing a novel concept for effective PDT.
Zeng et al. (2026) studied this question.