Mitochondria-Targeted Photodynamic Agents Drive Robust Pyroptosis by Caspase-3/GSDME Activation and Cardiolipin Externalization.

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/Co2 + 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 1O2-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.