Boosting Energy Deprivation by Synchronous Interventions of Glycolysis and Oxidative Phosphorylation for Bioenergetic Therapy Synergetic with Chemodynamic/Photothermal Therapy.

Bioenergetic therapy is emerging as a promising therapeutic approach. However, its therapeutic effectiveness is restricted by metabolic plasticity, as tumor cells switch metabolic phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) to compensate for energy. Herein, Metformin (MET) and BAY-876 (BAY) co-loaded CuFe2 O4 (CF) nanoplatform (CFMB) is developed to boost energy deprivation by synchronous interventions of glycolysis and OXPHOS for bioenergetic therapy synergetic with chemodynamic/photothermal therapy (CDT/PTT). The MET can simultaneously restrain glycolysis and OXPHOS by inhibiting hexokinase 2 (HK2) activity and damaging mitochondrial function to deprive energy, respectively. Besides, BAY blocks glucose uptake by inhibiting glucose transporter 1 (GLUT1) expression, further potentiating the glycolysis repression and thus achieving much more depletion of tumorigenic energy sources. Interestingly, the upregulated antioxidant glutathione (GSH) in cancer cells triggers CFMB degradation to release Cu+ /Fe2+ catalyzing tumor-overexpressed H2 O2 to hydroxyl radical (∙OH), both impairing OXPHOS and achieving GSH-depletion amplified CDT. Furthermore, upon near-infrared (NIR) light irradiation, CFMB has a photothermal conversion capacity to kill cancer cells for PTT and improve ∙OH production for enhanced CDT. In vivo experiments have manifested that CFMB remarkably suppressed tumor growth in mice without systemic toxicity. This study provides a new therapeutic modality paradigm to boost bioenergetic-related therapies.

H2O2 self-sufficient nanoplatform based on CeO2 QDs decorated MgO2 nanosheet for amplified chemodynamic therapy.

Chemodynamic therapy (CDT), which employs Fenton/Fenton-like agents to decompose hydrogen peroxide (H2O2) into toxic hydroxyl radical (•OH) to induce cancer cell apoptosis and necrosis, holds great promise in tumor therapy due to its high selectivity. Nevertheless, its efficiency is impaired by the insufficient intracellular H2O2 concentration and/or the insensitive response of Fenton/Fenton-like agents to the slightly acid tumor microenvironment (pH∼7.0-6.5). Herein, we develop a novel CDT reagent based on CeO2 quantum dot (QD) decorated MgO2 nanosheets engineered with cascade reactions to boost the intracellular H2O2 level and high pH-activated (pH = 6.5) characteristic for an enhanced CDT. Under the tumor microenvironment (pH = 6.5), MgO2 nanosheets that are highly reactive can react with H2O to produce nontoxic Mg2+ and abundant H2O2, boosting the intracellular H2O2 level. The self-generated H2O2 is subsequently converted into •OH by CeO2 QD, which is served as a relatively high pH-activated (pH = 6.5) Fenton-like agent. The sufficient intracellular H2O2 supply and sensitive response to the slightly acid tumor sites significantly improve the Fenton reaction, leading to the excellent in vivo CDT results with tumor growth inhibition effect. Our work presents a distinctive paradigm for self-boosting CDT efficacy.

Hydrogen peroxide self-sufficient and glutathione-depleted nanoplatform for boosting chemodynamic therapy synergetic phototherapy.

Chemodynamic therapy (CDT), which suppresses tumors via the conversion of endogenous hydrogen peroxide (H2O2) to highly toxic hydroxyl radicals (•OH), is deemed as a cutting-edge antitumor strategy. However, the insufficient endogenous H2O2 and up-regulated antioxidant glutathione (GSH) in the tumor microenvironment (TME) greatly impede the therapeutic effect of CDT. Herein, a versatile nanoplatform MgO2@SnFe2O4@PEG (MSnFeP) is elaborately fabricated for boosting CDT synergetic phototherapy. In the TME, the activation of MSnFeP contributes to in situ supply of H2O2, generation of •OH and consumption of GSH for boosted CDT. Furthermore, photothermal therapy (PTT) and photodynamic therapy (PDT) are simultaneously stimulated by near-infrared (NIR) light exposure on MSnFeP to increase the toxic free radical yield. This strategy not only amplifies the CDT efficacy hindered by H2O2 deficiency and GSH overexpression, but also further enhances the therapeutic effect with the combination of phototherapy.