A hydrogen sulfide-activated Pd@Cu₂O nanoprobe for NIR-II photoacoustic imaging of colon cancer and photothermal-enhanced ferroptosis therapy

Imaging guided cancer therapy is a comprehensive strategy that combines the diagnosis and treatment to eradicate tumors. Ferroptosis is a distinct programmed cell death and holds great potential in cancer therapy. In this study, a hydrogen sulfide (H₂S)-activated PEGylated Pd@Cu₂O core-shell nanocomposite (termed PCO) that in situ transformed into Pd@Cu_2-xS (termed PCS) at colorectal tumor tissues is developed for colorectal cancer photoacoustic (PA) imaging and photothermal-enhanced ferroptosis therapy in NIR-II window. The Cu⁺ on the surface of PCS can catalyze the Fenton-like reaction with overexpressed H₂O₂ in the colon tumor tissues, yielding hydroxyl radicals (·OH) and Cu²⁺. Moreover, the PCS accelerates the Fenton-like reaction to generate more ·OH. The PCS displays dual peroxidase- and glutathione oxidase-mimic enzymatic activity in weakly acidic tumor microenvironment (TME). Additionally, the glutathione depletion by Cu²⁺ results in the production of Cu⁺ and glutathione disulfide as well as the down-regulation of glutathione peroxidase 4. The interaction of polyunsaturated fatty acids with ·OH induces the up-regulation of lipid peroxides on cellular membrane, thereby causing ferroptosis. Hence, this study has developed the H₂S-activated PCO that in situ transforms into PCS, as a novel colon cancer diagnosis-treatment nanoprobe, for PA imaging guided precise diagnosis and efficient therapy of colon cancer.