Discovery of an asymmetric triphenylamine-based onium salt as a G-quadruplex-targeted fluorescent ligand for potential triple-negative breast cancer treatment.

Triple-negative breast cancer (TNBC) remains a therapeutic challenge due to its aggressive nature and lack of targeted receptors. This study introduced IMB, an asymmetric triphenylamine-based onium salt, as a novel mitochondrial G-quadruplex (mtG4)-targeted photosensitizer for photodynamic therapy (PDT). IMB demonstrated selective mitochondrial accumulation and strong mtG4-binding affinity, rendering it as a promising mtG4 fluorescent probe with near infrared (NIR) properties. Moreover, under white-light irradiation, the mtG4-bound IMB generated potent Type-I ROS, which may accelerate mtDNA damage, induce mitochondrial dysfunctions, leading to cell cycle arrest, and apoptosis. Functional assays revealed its potent antiproliferative effects, showing inhibition in cell migration, colony formation, and 3D spheroid growth. These findings established mtG4-targeted PDT as a promising strategy for TNBC, with IMB serving as a lead candidate for further preclinical development.