A cascade nanoplatform for intelligent response to tumor microenvironment and collaborative cancer therapy

Disulfiram (DSF), a new potential anticancer drug, has been shown to exhibit anticancer activity dependent on the formation of CuET, the chelation product of DSF with Cu²⁺. However, the poor stability of DSF and insufficient physiological concentration of Cu²⁺ hinder its practical application. To achieve the co-delivery of DSF and Cu²⁺ while overcoming the inefficiency of single chemotherapy, in this study, a cascade nanoplatform, DSF/Ce6@ZIF-8@CuO₂, was constructed by encapsulating DSF and chlorin e6 (Ce6, a photosensitizer) in zeolite imidazole framework-8 (ZIF-8, a nanocarrier) and then loading CuO₂, which self-supplied H₂O₂/O₂, onto DSF/Ce6@ZIF-8. By triggering the response of DSF/Ce6@ZIF-8@CuO₂ to the acidic tumor microenvironment, encapsulated DSF, Ce6 and CuO₂ were released to achieve multimodal synergistic treatment with enhanced DSF chemotherapy and chemodynamic/photodynamic therapy (CDT/PDT). In vitro and animal studies indicated that the designed DSF/Ce6@ZIF-8@CuO₂ has strong tumor-inhibitory effects and provides a promising paradigm for designing smart nanoplatforms.