Triple-Modal Mitochondrial G‑Quadruplex-Targeted Hemicyanine Photosensitizer SPNO for Imaging-Guided Tumor Phototheranostics

Mitochondrial DNA G-quadruplexes (mtDNA G4s) are promising therapeutic targets for cancer, driving the need for innovative theranostic agents. We report SPNO, a mitochondria-targeted near-infrared (NIR) hemicyanine derivative that integrates triple-modal functions: fluorescence imaging, G4 stabilization, and synergistic phototherapy. SPNO incorporates a triphenylphosphonium targeting moiety and a modified benzothiazole core with methoxy substitution and an extended π-bridge, enabling NIR absorption/emission and real-time tumor localization. It selectively binds and stabilizes mtDNA G4s, inducing G0 and G1 cell cycle arrest and metastasis inhibition. Under 685 nm laser irradiation, SPNO generates type I and II reactive oxygen species (ROS) with efficient photothermal conversion, achieving combined photodynamic therapy (PDT) and photothermal therapy (PTT). Unirradiated SPNO intrinsically suppresses tumor growth via G4 stabilization. In vivo, SPNO-mediated theranostics significantly inhibited breast tumors without systemic toxicity, showcasing a novel strategy for precision cancer treatment.