NIR-activatable proenzyme DSF/CuS@M for synergistic in situ chemotherapy/CDT/PTT/cuproptosis-based antitumor therapy

Nanozymes provide therapeutic benefits against a diverse range of malignant tumors. However, their antitumor potencies are seriously impaired by their low catalytic efficiencies and the off-target toxicities caused by their “always-on” catalytic activity. Herein, we developed multifunctional nanoparticles co-loaded with ultra-small copper sulfide nanoparticles (CuS NPs) and disulfiram (DSF) (DSF/CuS@M). These nanoparticles had peroxidase-like activity and served as (near-infrared) NIR-activatable proenzymes to achieve synergistic in situ chemotherapy, chemodynamic therapy (CDT), photothermal therapy (PTT), and cuproptosis-based antitumor therapy. DSF/CuS@M not only provided PTT as NIR-activatable proenzymes but also enabled complete DSF and Cu 2+ release. Non-toxic DSF was converted into diethyldithiocarbamic acid (DDC) through a glutathione (GSH)-mediated metabolic reaction, leading to the generation of cytotoxic Cu(DDC) 2 in situ , which enhanced cell apoptosis. Cu 2+ was converted into Cu + by GSH, and this Cu + catalyzed the conversion of H 2 O 2 into hydroxyl radicals (·OH) to induce CDT. Moreover, Cu + could also bind to dihydrolipoyl transacetylase (DLAT) in the tricarboxylic acid (TCA) cycle, thereby inducing cuproptosis. These results demonstrate that the NIR-activatable proenzyme developed in this study is effective and safe for synergistic therapy against malignant tumors.