Abstract

Glioblastoma multiforme (GBM), a highly prevalent and lethal form of malignant tumor, is typically treated with Temozolomide (TMZ), a chemotherapeutic agent. Nevertheless, the effectiveness of TMZ is hampered by inadequate cell entry, systemic adverse effects, and monotherapy constraints. Previous clinical studies have demonstrated that combination therapy can significantly enhance the therapeutic efficacy. Herein, we developed ultrasmall virus-inspired biodegradable tetrasulfide-bridged mesoporous organosilica coloaded with TMZ and indocyanine green (ICG) (designated as vMSTI) for fluorescence imaging-guided sonodynamic chemotherapy and glutathione (GSH) depletion, aiming to enhance the therapeutic efficiency of GBM. Once accumulated within the tumors, the vMSTI nanosystem efficiently entered tumor cells via "spike surface"-assisted endocytosis. Subsequently, intracellular overproduction of GSH within tumor cells triggered the degradation of vMSTI, resulting in the release of both TMZ and ICG, while simultaneously depleting intracellular GSH levels. Upon ultrasound (US) irradiation, the released ICG generated abundant reactive oxygen species (ROS) for sonodynamic therapy, which could be further potentiated by GSH depletion. Furthermore, released TMZ effectively elicited DNA damage to enable chemotherapy. Consequently, the vMSTI effectively triggered apoptosis, suppressing GBM growth under the guidance of fluorescence imaging. Our nanosystems offered a promising strategy for imaging-guided combination therapy for GBM.