An iridium(iii)-based photosensitizer disrupting the mitochondrial respiratory chain induces ferritinophagy-mediated immunogenic cell death

Cancer cells have a strategically optimized metabolism and tumor microenvironment for rapid proliferation and growth. Increasing research efforts have been focused on developing therapeutic agents that specifically target the metabolism of cancer cells. In this work, we prepared 1-methyl-4-phenylpyridinium-functionalized Ir(iii) complexes that selectively localize in the mitochondria and generate singlet oxygen and superoxide anion radicals upon two-photon irradiation. The generation of this oxidative stress leads to the disruption of the mitochondrial respiratory chain and therefore the disturbance of mitochondrial oxidative phosphorylation and glycolysis metabolisms, triggering cell death by combining immunogenic cell death and ferritinophagy. To the best of our knowledge, this latter is reported for the first time in the context of photodynamic therapy (PDT). To provide cancer selectivity, the best compound of this work was encapsulated within exosomes to form tumor-targeted nanoparticles. Treatment of the primary tumor of mice with two-photon irradiation (720 nm) 24 h after injection of the nanoparticles in the tail vein stops the primary tumor progression and almost completely inhibits the growth of distant tumors that were not irradiated. Our compound is a promising photosensitizer that efficiently disrupts the mitochondrial respiratory chain and induces ferritinophagy-mediated long-term immunotherapy.