Dongsheng Zhang, Xueli Zhang, Mengyuan Huang, Li‐Ya Niu, Kun‐Xu Teng, Qing‐Zheng Yang
ABSTRACT Photodynamic therapy (PDT)‐induced pyroptosis has attracted considerable interest as a strategy for cancer therapy, yet rational design of photosensitizers (PSs) that efficiently elicit pyroptosis remains underdeveloped. Herein, we report mitochondria‐targeted supramolecular PSs that simultaneously activate the caspase‐3/gasdermin E (GSDME) signal pathway and promote cardiolipin (CL) externalization to drive robust PDT–induced pyroptosis. A series of BODIPY‐based supramolecular PSs, containing quaternary‐ammonium moieties and N‐containing aromatic heterocyclic substituents, were rationally designed for mitochondrial accumulation and ROS generation. Upon light irradiation, these PSs elicit pronounced pyroptosis. Transmission electron microscopy and Calcein AM/Co 2 + imaging indicate that the mitochondrial membrane is significantly damaged, which probably is a critical event in the induction of pyroptosis. Immunofluorescence and Western blot analyses further demonstrate that 1 O 2 ‐mediated lipid peroxidation activates the caspase‐3/GSDME pathway and promotes CL externalization, facilitating mitochondrial pore formation and amplified release of mitochondrial contents. This positive feedback loop sustains caspase‐3 activity and pore formation, committing cells to pyroptotic death. The PSs exhibit excellent antitumor efficacy in tumor‐bearing mouse models.