Inhibition of NADP(H) supply by highly active phosphatase-like ceria nanozymes to boost oxidative stress and ferroptosis

Ceria (CeO₂) with phosphatase-like activity is widely recognized as one of the promising nanozymes. In general, shrinkage of the sizes of CeO₂ can generate large active surface areas for dephosphorylation reactions. However, synthesizing CeO₂ with an ultra-small structure while retaining its surface activity and avoiding its aggregation for use in non-redox biological applications has been a continuous challenge. Herein, a phosphatase-mimicking nanozyme CeO₂ with ultra-small, excellent dispersibility, and accessibility, and largely exposed {111} facet was synthesized via a facile one-pot approach. In contrast to previous reports, which focus on enhancing the ·OH-induced cellular damage by peroxidase- or oxidase-like activity of CeO₂, the present work demonstrates the phosphatase-like activity of CeO₂ for boosting ferroptosis by disrupting cellular homeostasis. Cancer cells require high levels of nicotinamide adenine dinucleotide phosphate (NADP(H)) to enhance GSH synthesis and resist to ferroptosis. By virtue of the phosphatase-like activity, the obtained CeO₂ could sustainably dephosphorylate NADP(H) and effectively inhibit the intracellular biosynthesis of GSH. Our results showed that using CeO₂ as a phosphatase-mimicking nanozyme to deplete NADP(H) and its synthetic precursor glucose-6-phosphate (G6P) could attenuate the repair mechanisms under oxidative stress via indirectly inhibiting the supply of intracellular GSH and enhancing the occurrence of ferroptosis. The finding offers new insights into the regulation of ferroptosis by high-efficiency non-redox nanozymes, which could pave the way for the development of phosphatase-mimicking nanozymes.