Synergistic glycolysis disturbance for cancer therapy by a MOF-based nanospoiler

Abstract

Increased glycolysis for promoting adenosine triphosphate (ATP) generation is one of the hallmarks of cancer. Although reducing glucose intake or depriving cellular glucose can delay the growth of tumors to some extent, their therapeutic efficacy is a highly needed improvement for clinical translation. Herein, we found that mannose synergistic with glucose oxidase (GOx) can induce cell death by ATP inhibition, autophagy activation, and apoptosis protein upgradation. By using biodegradable zeolitic imidazolate frameworks (ZIF-8) as a nanocarrier (denoted as ZIF-8/M&G), the mannose and GOx can accumulate at the tumor site while having no obvious long-term toxicity. At the tumor site, GOx inhibits glycolysis by converting glucose and oxygen to H₂O₂ and gluconic acid, realizing oxidation therapy and expediting the degradation of the pH-responsive ZIF-8 nanoparticles, respectively. Simultaneously, mannose disturbs sugar metabolism and reduces oxygen consumption, which in turn promotes the GOx oxidation process. The concerted glycolysis inhibition through interactions between mannose and GOx endows ZIF-8/M&G nanospolier with excellent therapeutic efficacy bothin vitro and in vivo. Synergistic glycolysis disturbance by the designed nanospoiler in this work proposes a versatile approach for metabolism disturbance to tumor treatment.

Graphical abstract

Keywords

Glycolysis disturbance / Energy deprivation / Drug delivery / Zeolitic imidazolate frameworks / Metal-organic frameworks