Photochemical Generation of Peroxynitrite: Concurrent Inhibition of Glycolysis and Glutamine Metabolism for Enhanced Metabolic Therapy

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 <i>in vitro</i> and <i>in vivo</i> 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.