Mitochondria-targeted coumarin-hemicyanine dye: NIR image-guided synergistic PDT/PTT with spatiotemporal controllability

Phototheranostics, integrating real-time imaging with targeted therapy, represents a breakthrough in precision cancer treatment. However, conventional agents suffer from limited tissue penetration due to short-wavelength excitation/emission (<650 nm) and suboptimal efficacy from monomodal therapeutic mechanisms. To overcome these limitations, we engineered NCCy , a cationic donor-π-acceptor dye combining triphenylamine donors, coumarin-hemicyanine acceptors, and indole-derived cations. This design extends -conjugation to achieve red and near-infrared dual-channel fluorescence imaging capabilities, while leveraging the 60 mV mitochondrial membrane potential gradient for tumor-selective targeting. Under 660 nm irradiation, NCCy simultaneously generates singlet oxygen and hyperthermia, enabling synergistic photodynamic-photothermal therapy. In vitro studies demonstrated dual-channel fluorescence imaging-guided mitochondrial localization and reactive oxygen species/heat co-generation, inducing apoptosis. In 4T1 tumor-bearing mice, NCCy achieved rapid tumor accumulation (<1 h) with sustained retention, facilitating near-infrared image-guided therapy that suppressed 68% of tumor growth without systemic toxicity, as confirmed by histopathological analysis. This work establishes a molecular blueprint for deep-tissue-penetrating, multimodal phototheranostics, offering a clinically translatable strategy for precision oncology through spatiotemporally controlled treatment activation and microenvironment-responsive therapeutic synergy.