Enhanced Immunotherapy for Glioblastoma Using a Cholesterol Oxidase-Loaded, Pd-Doped Cu₃N Nanozyme-Based Multimodal...

Glioblastoma multiforme (GBM) remains one of the most lethal brain tumors, characterized by metabolic plasticity, redox adaptability, an immunosuppressive microenvironment, and limited therapeutic penetration across the blood-brain barrier (BBB). Here, we present a multifunctional Cu₃PdN@CR nanoplatform that integrates metabolic disruption with sonodynamic activation to potentiate ferroptosis and cuproptosis while augmenting immunotherapy. The phase transition from Cu₃N to Pd-doped Cu₃PdN converts the material from a semiconductor to a semimetal with a narrowed band gap, conferring enhanced redox activity for glutathione (GSH) depletion and reactive oxygen species (ROS) generation, thereby inducing oxidative imbalance and mitochondrial collapse. Conjugation with cholesterol oxidase (COD) further depletes cholesterol and downregulates PD-L1, eliciting metabolic stress and immunogenic remodeling. The RVG29 peptide facilitates BBB penetration and glioma targeting, while ultrasound (US) stimulation amplifies ROS production. This cascade triggers immunogenic cell death (ICD), evidenced by calreticulin exposure and ATP release, which in turn promotes dendritic cell maturation and CD8+ T-cell infiltration. In orthotopic GBM models, Cu₃PdN@CR significantly suppresses tumor growth and prolongs survival without systemic toxicity. Collectively, this study establishes a BBB-permeable, US-augmented nanoplatform as a promising ferroptosis/cuproptosis-based strategy for effective GBM therapy.