A Bivalent Iridium(III) Complex Toolkit for Mitochondrial DNA G-Quadruplex-Targeted Theranostics

The G-quadruplex (G4) is an important diagnostic and therapeutic target in cancers, but the development of theranostic probes for subcellular G4 s remains challenging. In this work, we report three G4-targeted theranostic probes by conjugating a pyridostatin-derived G4 ligand to G4-specific iridium(III) complexes with desirable photophysical properties. These probes showed specifically enhanced luminescence to mitochondrial G4 in triple-negative breast cancer (TNBC) cells. Of note, complex 3 exhibited NIR emission and the ability to discriminate TNBC cells and normal breast cells. Furthermore, these probes showed much higher PDT toxicity in TNBC cells through ROS-induced apoptosis, where complex 3 exhibited a type I/II hybrid PDT effect with the potential to overcome hypoxia. These results demonstrate that these complexes are multicolor and modular phototheranostic probes for DNA G4s. We believe that this work offers a multifunctional theranostic toolkit for unmasking subcellular DNA G-quadruplex functions. © 2025 Wiley-VCH GmbH.