Biocompatible nanozyme with dual catalytic activities for high-performance multimodality therapy against glioblastoma

Nanozymes based on metals have been regarded as a promising candidate in the metabolic reprogramming of low-survival, refractory glioblastoma multiforme (GBM). However, due to size limitations, nanozymes struggle to balance catalytic activity with the ability to cross the blood-brain barrier (BBB), limiting their efficiency in GBM therapy. Herein, we establish a hybrid nanocluster, AuMn NCs, by cross-linking ultrasmall nano-gold (Au) and manganese oxide (MnO₂), which overcomes the size requirement conflict for integrating catalytic activities, long-period circulation, photothermal effect, glucose consumption, and chemodynamic effect for multimodality treatment against GBM. After administered intravenously, the overall large-size AuMn NCs can escape kidney filtration and cross the BBB for GBM accumulation. Then the individual ultrasmall nano-MnO₂ components effectively catalyze H₂O₂ degradation as catalase to produce oxygen, which is utilized by individual ultrasmall nano-Au components to consume glucose as glucose oxidase for starvation therapy. The H₂O₂ generated during Au-catalyzed glucose consumption further facilitates MnO₂ catalytic activity. Such positive feedback overwhelmingly intervenes in the glucose metabolism of GBM. Concurrently, clustered Au-induced photothermal effect and released Mn²⁺-induced chemodynamic effect further contribute to eliminating GBM cells. The versatile clustered nanozyme offers a feasible strategy for the multimodality intervention of GBM.