A dual lock-and-key activated theranostic tool for highly specific near-infrared imaging and photodynamic/chemodynamic synergistic therapy of hepatocellular carcinoma.

Early and precise diagnosis of hepatocellular carcinoma (HCC) is crucial for improving patient prognosis and survival. However, the complexity of HCC often limits the specificity of probes that rely on a single biomarker. To address this, we developed HTQ-Fc, a novel dual-responsive fluorescent probe designed for HCC diagnosis and therapy. This probe was uniquely activated by the synergistic action of two distinct biomarkers: carboxylesterase (CE) and viscosity, both of which were elevated in HCC. HTQ-Fc was engineered by linking a CE-cleavable unit to a viscosity-sensitive near-infrared (NIR) photosensitizer. This design allowed for a dual-lock activation, leading to a strong NIR fluorescent signal and the production of therapeutic reactive oxygen species. In cell studies, activated HTQ-Fc precisely differentiated hepatoma cells from other cell types and distinguished HCC from liver injury, showing superior specificity compared to single-parameter probes. Furthermore, activated HTQ-Fc efficiently generated 1O2 and ˙OH, which effectively induced apoptosis and ferroptosis in cancer cells. In vivo studies confirmed that HTQ-Fc could provide real-time HCC-specific visualization and significant tumor suppression through NIR fluorescence-guided photodynamic/chemodynamic synergistic therapy. This study showcases HTQ-Fc's potential as a powerful theranostic tool with promising clinical applications.