Cascade-activatable NIR-II fluorescent carbonic anhydrase inhibitors for imaging-guided cuproptosis/chemodynamic combination therapy of colorectal cancer

Colorectal cancer (CRC) is among the malignancies with the highest morbidity, and accurate diagnosis and therapy are essential for improving patient survival. However, CRC is usually diagnosed at an advanced stage, and complete resection of the tumor lesion during treatment is difficult. Herein, we develop a cascade-activatable NIR-II fluorescent inhibitor (Cu@IR783-CAI) for imaging-guided cuproptosis/chemodynamic combination therapy of CRC. Cu@IR783-CAI is synthesized by sequentially modifying a copper complex and a benzenesulfonamide moiety onto NIR-II fluorescent dye IR783. The NIR-II fluorescence signal is quenched by the copper complex <i>via</i> a donor-excited photoinduced electron transfer (d-PeT) process under physiological conditions. In the CRC microenvironment, the overexpressed hydrogen sulfide (H₂S) can react with the copper complex to generate copper sulfide, which hinders the d-PeT process and recovers the NIR-II fluorescence signal. Furthermore, Cu@IR783-CAI targets carbonic anhydrase IX (CA IX), which is overexpressed on the surface of tumor cells, thereby restricting intramolecular rotation and further enhancing the NIR-II fluorescence signal, thus achieving cascade activation. In addition, the copper complex of Cu@IR783-CAI can simultaneously trigger cuproptosis and chemodynamic therapy within tumor cells, demonstrating satisfactory anticancer efficacy both <i>in vitro</i> and <i>in vivo</i>. Thus, our study provides a smart NIR-II fluorescent CA inhibitor with cascade-activatable features for CRC theranostics.