A Mitochondria-Targeted Iridium(III) Complex as a Potent Type-I/II Photosensitizer for Pyroptosis-Based Breast Cancer Therapy.

Abstract

Type-I photodynamic therapy (PDT) is a promising strategy for treating hypoxic tumors because it overcomes the oxygen dependence of traditional PDT. However, the rational design of a potent Type-I photosensitizer that simultaneously achieves subcellular organelle targeting and activates the pyroptotic cell-death pathway remains a formidable challenge. Herein, we report the development of a "Swiss-army-knife" iridium(III) complex, termed Mito-Ir, that concurrently integrates mitochondria targeting, phosphorescence imaging, Type-I/II reactive oxygen species generation, photocatalytic oxidation of 1,4-dihydronicotinamide adenine dinucleotide (NADH) and pyroptosis induction, offering a "one-for-all" platform for high-performance breast-cancer PDT. Upon light irradiation, Mito-Ir triggers severe mitochondrial dysfunction, activating the caspase-3/GSDME pathway to induce pronounced pyroptosis. This pathway not only overcomes apoptosis resistance but also elicits immunogenic cell death through the release of cytokines and damage-associated molecular patterns, thereby activating antitumor immunity. Both in vitro and in vivo studies confirmed its potent antitumor efficacy, underscoring its potential as a pioneering pyroptosis-based therapeutic strategy for breast cancer.