Tumor Microenvironment-Responsive Nanoplatform of Cu-Doped ZIF-8 Dual-Loaded with ICG and DOX for Photothermal-Enhanced Chemodynamic Therapy/Chemotherapy

Targeting tumor-specific characteristics of acidic microenvironment, elevated H2O2 levels, and thermosensitivity, this study proposed and developed a copper-doped ZIF-8 nanoplatform coloaded with indocyanine green (ICG) and doxorubicin hydrochloride (DOX), designated as Cu-ZIF-8@ICG&DOX (CZID), to establish a multimodal therapeutic system integrating chemodynamic therapy, photothermal therapy, and chemotherapy. Results showed that the 25% copper doping level optimized the structure, achieving 7.46% actual doping content while limiting the average nanoparticle size to 99.6 nm. Dual loading of ICG and DOX induced morphological transition to spherical core–shell architectures, as confirmed by zeta potential reversal, with maximum drug loading capacities of 23.01 μg/mg for ICG and 122.43 μg/mg for DOX. The ZIF-8 framework exhibited pH-responsive degradation under acidic conditions. Released Cu2+ ions mediated continuous hydroxyl radical generation through glutathione-depletion redox cycling, confirming chemodynamic efficacy. Under 808 nm laser irradiation, ICG enabled enhanced photothermal conversion, showing concentration- and power-dependent temperature elevation. Cellular assays revealed efficient CZID internalization by MCF-7 cells, generating significantly higher intracellular reactive oxygen species levels under irradiation and more intense dead cell staining compared to CZI and CZD groups. Such an enhancement was attributed to photothermally accelerated ZIF-8 degradation, promoting Cu2+ ions and DOX release, thereby strengthening chemodynamic–chemotherapy synergy. At the working concentration of 50 μg/mL, CZID induced 95.36% apoptosis in MCF-7 cells while maintaining over 70% viability in MCF-10A normal cells, validating its precise antitumor potential.