Targeting mitochondrial G-quadruplex DNA with a theragnostic small molecule for cervical Cancer imaging and therapy.

Abstract

Mitochondria are emerging as critical hubs for cancer therapeutics, yet the development of agents that simultaneously enable real-time imaging and targeted therapy remains a formidable challenge. Here we report LN1, a smart theranostic small molecule designed to selectively target mitochondrial G-quadruplex (mtG4) DNA through a triphenylphosphonium (TPP) moiety integrated with a triphenylamine-derived fluorescent scaffold. LN1 exhibits high-affinity binding to mtG4 structures (Kd = 0.2 μM) with a 1:2 stoichiometry, leading to a pronounced fluorescence turn-on response via restriction of intramolecular rotation. This optical property enables real-time, subcellular tracking of LN1 localization to mitochondria in live cancer cells with exceptional specificity. Functionally, LN1 stabilizes mtG4s, disrupts mitochondrial homeostasis, elevates reactive oxygen species, depletes ATP, and induces S-phase arrest, ultimately triggering robust apoptosis through activation of the caspase-3/7/9 and PARP pathways. In vivo, LN1 achieves selective tumor accumulation, enables high-contrast fluorescence imaging of xenografted tumors, and exhibits antitumor efficacy comparable to that of topotecan. By integrating diagnostic imaging and targeted anticancer activity within a single molecular framework, this work establishes a new paradigm for mitochondria-targeted theranostics and highlights mtG4 DNA as a clinically actionable vulnerability in cancer.