Cu–phytic acid nanozyme-induced cuproptosis therapy for the inhibition of tumor growth

Cuproptosis has recently received much attention in cancer treatment. However, copper ionophores do not show any obvious clinical efficacy. Although some Cu-based and copper ionophore-loaded nanomaterials have been applied to induce cuproptosis, it is difficult to achieve their clinical translation as they are limited by their complicated composition, harsh synthesis conditions, requirement of external stimuli, and potential biotoxicity. Phytic acid, a naturally occurring organic phosphorus carbohydrate, possesses a distinct antineoplastic effect on multiple types of cancer and high biocompatibility. Based on metal-phosphonate coordination, a novel Cu-phytic acid nanozyme (denoted as CP) with a pH/GSH dual response was fabricated by a "one-pot" method. CP with three enzyme-mimicking activities enhanced cuproptosis therapy through GSH depletion, reactive oxygen species augmentation, hypoxia relief and the attenuation of glycolysis. As a proof of concept, Elesclomol (a copper ionophore)-resistant A549 cells were used to investigate CP-induced cuproptosis for the inhibition of tumor growth <i>in vitro</i> and <i>in vivo</i>.