Carboxylesterase-Triggered Theranostic Agent: Advancing Near-Infrared Imaging and Therapeutic Efficacy in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) poses a global challenge due to the lack of accurate early stage detection methods. Carboxylesterase (CE), a key HCC biomarker, presents an ideal target for HCC diagnosis. Herein, we developed a novel CE-sensitive fluorescent probe ( HFP-CE ) that offered powerful near-infrared fluorescence signals and a potent synergistic photodynamic/chemodynamic therapeutic effect against HCC. This probe was synthesized by linking ferrocenecarboxylic acid (a Fenton reagent) to HFP-OH (a photosensitizer) through a self-eliminating spacer. This activation enabled ratiometric fluorescence imaging of CE, allowing for specific differentiation of HCC cells from others, exceeding the capabilities of commercial kits. Moreover, HFP-CE could generate 1 O 2 and • OH upon CE activation in vitro, triggering both apoptosis and ferroptosis in cancer cells. Remarkably, HFP-CE enabled real-time tumor visualization and effective tumor growth inhibition in vivo. This study showcased the promise of HFP-CE as a versatile tool for advancing precision medicine in HCC.