Phosphorescent iridium complexes activated by endogenous zinc as a mitochondrial DNA nuclease for stimulation of the cGAS-STING pathway

Zinc is a crucial element in cellular processes, and its homeostasis has intricate relationships with the initiation, progression, and therapeutic intervention of cancer. Activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been proven to be an effective strategy for cancer immunotherapy. Herein, we report four phosphorescent iridium complexes (Ir1-Ir4) with zinc chelating ligands. Among them, Ir1 can bind and image mitochondrial chelatable zinc ions <i>via</i> phosphorescence-lifetime responses, consequently modulating the expression of zinc-regulatory proteins. Furthermore, the <i>in situ</i> formed heteronuclear metal complex Ir1-Zn₂ shows nuclease mimetic activities, capable of hydrolyzing mitochondrial DNA (mtDNA) to release mtDNA fragments for the activation of the cGAS-STING pathway. In conclusion, we designed a mitochondria-targeting phosphorescent Ir(iii) complex with dual functions in dysregulation of zinc homeostasis and generation of nuclease <i>in situ</i>, which provides an innovative approach to stimulate the cGAS-STING pathway.