Acid triggering highly-efficient release of reactive oxygen species to block mitochondrial-mediated homeostasis...

A pivotal pathway of photodynamic therapy (PDT) is to prompt mitochondrial damage by reactive oxygen species (ROS) generation, thus leading to cancer cell apoptosis. However, mitochondrial autophagy is induced during such a PDT process, which is a protective mechanism for cancer cell homeostasis, resulting in undermined therapeutic efficacy. Herein, we report a series of meticulously designed donor (D)-π-acceptor (A) photosensitizers (PSs), characterized by the strategic modulation of thiophene π-bridges, which exhibit unparalleled mitochondrial targeting proficiency. Notably, TTBI within this series possesses remarkable ROS generation capability, which can directly trigger mitochondrial depolarization, thus effectively inducing apoptosis in cancer cells. Meanwhile, the damaged mitochondria activate the mitophagy process, which further boosts the ROS generation of the TTBI owing to the acidic environment in the lysosome, ultimately inducing lysosomal membrane permeability (LMP), thereby blocking the protective autophagy route and promoting extra apoptotic cell death. Accordingly, TTBI disrupts the integrity of mitochondrial and lysosome, leveraging a synergistic interplay between cellular compartments to achieve more potent apoptosis. This work provides new insights to overcome the limitation of PDT efficacy imposed by mitochondrial autophagy.