Synergistic Heterojunction/Cu─N Coordination Engineering Drives Cuproptosis and PANoptosis for Sonodynamic Glioblastoma Therapy.

Abstract

Glioblastoma (GBM) remains one of the most lethal intracranial malignancies due to its diffuse invasiveness and inevitable recurrence. Sonodynamic therapy (SDT) offers a noninvasive strategy for deep-tissue tumor ablation; however, its efficacy is often limited by rapid electron-hole recombination in conventional sonosensitizers, resulting in insufficient reactive oxygen species (ROS). In this study, a biomimetic nanosonosensitizer is rationally engineered via synergistic type II heterojunction interface construction and Cu─N coordination electronic activation. By anchoring Cu─N coordinated carbon dots (Cu-CDs) onto two-dimensional (2D) nanosheets, the compact heterojunction enables spatial charge separation, while Cu─N motifs act as kinetic promoters to accelerate interfacial electron transfer. This co-engineering strategy markedly enhances ultrasound (US) -triggered multi-ROS generation, leading to amplified oxidative stress. Biologically, intracellular copper overload triggers cuproptosis via lipoylated protein aggregation, whereas ROS burst induces PANoptosis-like cell death. Importantly, the synergistic death programs promote robust immunogenic cell death (ICD) with elevated Damage-associated molecular patterns (DAMPs) release/exposur, thereby activating antitumor immunity and contributing to enhanced therapeutic efficacy against GBM. This work provides new insights into the rational design of highly efficient sonosensitizers and offers new dimensions for precision SDT-based glioma sono-immunotherapy.