Single‐Atom Magnesium Nanozymes Orchestrate Redox Homeostasis and Controlled Autophagy for Glioblastoma Therapy

ABSTRACT Glioblastoma (GBM) is one of the most aggressive and infiltrative brain tumors, characterized by dismal prognosis due to therapeutic resistance and the restrictive blood–brain barrier (BBB). Abnormal redox balance contributes to GBM progression and therapy resistance, suggesting that modulating reactive oxygen species (ROS) could be a promising therapeutic strategy. Here, we developed an atomically engineered magnesium (Mg) single‐atom nanozyme (MgSA) anchored to nitrogen‐doped carbon (NC) frameworks, in which robust Lewis acidic Mg centers with s/p‐band electronic structures are transformed into highly active enzyme‐mimicking catalytic sites. The MgSA exhibits integrated peroxidase‐, oxidase‐, catalase‐, and notably NADH oxidase‐like activities, enabling precise control of intracellular ROS levels and disrupting redox homeostasis by inhibiting glutathione (GSH) and adenosine triphosphate (ATP) regeneration. Density functional theory calculations reveal a low‐energy reaction pathway underlying its multienzyme mimicry. The induced oxidative stress triggers autophagic pathways to clear the damaged organelles and hence substantially suppresses the progression of GBM. MgSA is functionalized with angiopep‐2 (Ang‐pMgSA) for efficient brain delivery, permitting BBB penetration via LRP1 receptors and for targeting gliomas. Collectively, this work establishes MgSA as a biogenic single‐atom catalytic platform for redox‐modulated autophagy therapy and highlights Mg single atoms as a potential candidate for neuro‐oncology applications.