Dual-pathway glycolysis inhibition for boosting bioenergetic therapy synergistic with chemodynamic/photothermal therapy

Energy is the basis of survival for all organisms, and proliferative tumuor cells rely primarily on glycolysis to obtain energy to meet high bioenergetic demands. Glycolysis inhibition has emerged as a key target for cancer therapeutic applications. However, the therapeutic efficiency of glycolysis suppression is restrained by the mutual compensation of multiple energy-generating pathways and biological barriers in the complex tumuor microenvironment (TME). In this study, we developed polydopamine (PDA)-coated porous CeO 2-x nanorods with metformin (MET) and glucose oxidase (GOx) co-loading and bovine serum albumin (BSA) encapsulation (denoted as CPGMB) for dual-pathway glycolysis inhibition-boosted bioenergetic therapy with photothermal/chemodynamic therapy (PTT/CDT). MET and GOx are released due to the weakly acidic TME and the photothermal effect to suppress glycolysis via hexokinase 2 (HK2) inhibition and glucose deprivation pathways, respectively. Interestingly, H 2 O 2 produced by GOx-catalysed glucose oxidation was converted into O 2 by Ce 4+ , resulting in closed-loop glucose depletion, further potentiating glycolysis restraint via hypoxia relief. Meanwhile, H 2 O 2 could also be transformed into •OH by Ce 3+ for CDT. Furthermore, the photothermal effect of CPGMB ablated the cancer cells and amplified •OH production. In vitro and in vivo experiments confirmed the anti-tumour efficacy and biosafety of CPGMB. This study presents a novel strategy for a synergistic bioenergetic antitumour therapy.