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A Degradable Nanoplatform Integrating Glucose Oxidase and Copper Selenide for Near-Infrared-Enhanced Multimodal
Yong Zhang1, Lei Xue2, Lin Shi1
1Department of Pulmonary, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Abstract:
Lung cancer remains a leading cause of cancer-related mortality worldwide, with therapeutic outcomes frequently constrained by drug resistance, tumor heterogeneity, and systemic toxicity. Multimodal synergistic therapy has emerged as a promising strategy to address these challenges. In this study, we developed a biodegradable nanosystem, designated CSZG, which integrates glucose oxidase (GOx) and copper-rich copper selenide (Cu2-x Se) within a ZIF-8 nanocarrier for lung cancer therapy. CSZG exhibited pH-responsive GOx release, favorable colloidal stability, and retained glucose-responsive catalytic activity of GOx. GOx supplied hydrogen peroxide (H2O2) through glucose oxidation, while Cu+ catalyzed the conversion of H2O2 into cytotoxic hydroxyl radicals (•OH) under near-infrared (NIR) irradiation, thereby enhancing chemodynamic therapy. Electron spin resonance analysis directly confirmed NIR-enhanced •OH generation, particularly under acidic conditions. In addition, CSZG + NIR induced copper-dependent mitochondrial dysfunction with cuproptosis-associated features, as evidenced by aggregation of dihydrolipoamide S-acetyltransferase, down-regulation of ferredoxin 1 , depletion of Fe-S cluster proteins, and partial reversal by tetrathiomolybdate. The Cu2-x Se-containing platform also promoted macrophage polarization toward an M1-like phenotype. In vivo, CSZG + NIR achieved a tumor inhibition rate of 91.7% and demonstrated favorable short-term systemic biosafety under the tested therapeutic conditions. Collectively, these findings highlight CSZG as a promising multimodal therapeutic platform for lung cancer.
Insights
This study introduces CSZG, a novel nanosystem for lung cancer therapy. It combines glucose oxidase and copper selenide to generate cytotoxic radicals, showing significant tumor inhibition and good biosafety.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Lung cancer is a major cause of death, often worsened by drug resistance and toxicity.
- Multimodal synergistic therapy offers a promising approach to overcome these limitations.
Purpose of the Study:
- To develop a biodegradable nanosystem (CSZG) for enhanced lung cancer treatment.
- To investigate the synergistic effects of glucose oxidase (GOx) and copper selenide (Cu2-xSe) within a ZIF-8 nanocarrier.
Main Methods:
- CSZG nanosystem fabrication integrating GOx and Cu2-xSe in ZIF-8.
- Assessment of pH-responsive GOx release and catalytic activity.
- Evaluation of chemodynamic therapy via NIR-enhanced hydroxyl radical generation.
- Analysis of copper-induced mitochondrial dysfunction and cuproptosis.
- Investigation of macrophage polarization.
- In vivo tumor inhibition and biosafety studies.
Main Results:
- CSZG demonstrated pH-responsive GOx release and retained glucose-responsive activity.
- NIR irradiation significantly enhanced hydroxyl radical generation, particularly in acidic tumor microenvironments.
- CSZG + NIR induced cuproptosis-like mitochondrial dysfunction and M1-like macrophage polarization.
- In vivo studies showed a 91.7% tumor inhibition rate with favorable short-term biosafety.
Conclusions:
- CSZG is an effective multimodal therapeutic platform for lung cancer.
- The nanosystem leverages synergistic effects for enhanced tumor killing and immune modulation.
- CSZG shows potential for overcoming challenges in current lung cancer treatments.
