Rational design of ultrabright NIR-II nanofluorophores with enhanced photothermal conversion efficiency for targeted chemodynamic-hypothermal photothermal therapy of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) ranks among the most prevalent and lethal cancers worldwide. Near-infrared II (NIR-II) phototheranostic strategy provides the potential for non-invasive diagnosis and treatment of HCC. However, the NIR-II-based phototheranostic for HCC encounters two primary challenges: the limited photothermal conversion efficiency (PCE) requiring high-temperature hyperther-mia, and low quantum yields leading to imprecise therapeutic localization and non-specific uptake in normal liver tissue, compromise the selectivity, safety, and efficacy of the NIR-II phototheranostic. This study employing molecular engineering systematic optimization of three molecules (IR-FDBT, IR-FDA, IR-FDHT) yielded the optimal IR-FDHT to address these limitations. IR-FDHT features thienothiophenes-functionalized alkyl chains, which alleviate aggregation-caused quenching (ACQ) in aqueous media and enhance the accuracy of NIR-II fluorescence imaging upon tumor accumulation. Additionally, synergistic S···N/S···O intramolecular interactions in IR-FDHT enhance π-conjugation and conforma-tional locking, yielding a significant bathochromic shift and a high PCE of 52.5%, when synergistically integrated with mild hypothermal phototherapy (HPTT) and en-hanced chemodynamic therapy (ECDT), markedly improves phototherapeutic efficacy and safety. Fur-thermore, the self-assembled FDHT-SP94-Fc nanoparticles, which integrate optimized photophysical properties with biological targeting capabilities, markedly enhance phototheranostic specificity and efficacy and provide a paradigm for the selectivity, safety, and effectiveness of HCC NIR-II photo-theranostics.