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Photochemical Generation of Peroxynitrite: Concurrent Inhibition of Glycolysis and Glutamine Metabolism for Enhanced
Lizhen Yuan1, Liang Yang1, Wen Song2
1State Key Laboratory of Geomicrobiology and Environmental Changes, Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China.
Abstract:
Disrupting homeostasis within tumor cells by interfering with their diverse metabolic pathways is an attractive tumor treatment method. However, current methods generally focus on one pathway within tumor cells, such as glycolysis or the glutamine (Gln) metabolic pathway, overlooking potential strong correlations between different cellular pathways and preventing a comprehensive blockade of the tumor energy supply, thereby compromising therapeutic efficacy. Herein, a photochemistry-activated peroxynitrite (ONOO-) nanogenerator, capable of simultaneously inhibiting glycolysis and Gln metabolism in tumor cells, is proposed to achieve enhanced metabolic therapy. Specifically, the ONOO- nanogenerator is constructed by loading the thermally sensitive nitric oxide (NO) donor BNN-6 onto dual-function Prussian blue (PB) nanocubes through electrostatic interaction, followed by coating with tumor cell membranes to achieve homologous targeting. Under near-infrared light irradiation, PB decomposes hydrogen peroxide (H2O2) to produce oxygen, while the converted heat induces BNN-6 decomposition to generate NO. Subsequently, NO reacts with oxygen to form nitrite, and then with H2O2 to yield ONOO- under acidic conditions. ONOO- achieves simultaneous inhibition of glycolysis and Gln metabolism through the nitration of key proteins. More importantly, the former effectively reduces lactate levels, and the latter increases Gln levels, which both, in turn, remodel the tumor microenvironment and stimulate a strong immune response. The in vitro and in vivo data demonstrated that these changes significantly inhibited the growth and spread of primary and distant metastatic tumors in a mouse model. This approach takes advantage of tumor-specific physicochemical properties to enable localized and highly efficient ONOO- synthesis, offering promise for enhanced metabolic therapy.
Insights
This study introduces a novel nanogenerator that simultaneously blocks tumor cell energy pathways, glycolysis and glutamine metabolism, enhancing cancer therapy effectiveness. This approach disrupts tumor homeostasis and stimulates an immune response for improved treatment outcomes.
Area of Science:
- Biomedical Engineering
- Cancer Therapy
- Nanotechnology
Background:
- Disrupting tumor cell homeostasis via metabolic pathway interference is a promising cancer treatment strategy.
- Current therapies often target single pathways, limiting comprehensive blockade of tumor energy supply and compromising efficacy.
- Interconnectedness of cellular metabolic pathways necessitates multi-targeted approaches for enhanced therapeutic outcomes.
Purpose of the Study:
- To develop a novel photochemistry-activated peroxynitrite (ONOO-) nanogenerator for simultaneous inhibition of glycolysis and glutamine metabolism in tumor cells.
- To achieve enhanced metabolic therapy by creating a comprehensive blockade of tumor energy supply.
- To investigate the potential of this nanogenerator in remodeling the tumor microenvironment and stimulating an immune response.
Main Methods:
- Fabrication of ONOO- nanogenerator using Prussian blue (PB) nanocubes loaded with nitric oxide (NO) donor BNN-6, coated with tumor cell membranes.
- Photochemical activation using near-infrared light to trigger PB decomposition, NO generation, and subsequent ONOO- synthesis under acidic conditions.
- Evaluation of ONOO- mediated simultaneous inhibition of glycolysis and glutamine metabolism, protein nitration, and impact on lactate and glutamine levels in vitro and in vivo.
Main Results:
- The nanogenerator successfully generated ONOO- upon near-infrared irradiation, simultaneously inhibiting glycolysis and glutamine metabolism.
- ONOO- mediated nitration of key proteins led to reduced lactate and increased glutamine levels, remodeling the tumor microenvironment.
- Significant inhibition of primary and metastatic tumor growth was observed in vivo, alongside a stimulated immune response.
Conclusions:
- The developed ONOO- nanogenerator offers a promising strategy for enhanced metabolic therapy by simultaneously targeting key tumor metabolic pathways.
- Leveraging tumor-specific properties for localized ONOO- synthesis enhances therapeutic efficiency and minimizes off-target effects.
- This approach holds potential for improving cancer treatment by disrupting tumor energy supply and eliciting a potent anti-tumor immune response.
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