Multifunctional Mesoporous Silicon Nanoparticles for MRI-Based Diagnostic Imaging and Glioma Therapy.

To overcome the limited efficacy of chemodynamic therapy (CDT) caused by insufficient hydrogen peroxide (H2O2) in the tumor microenvironment, we engineered a glutathione (GSH)-responsive multifunctional nanosystem, HCTG-C, based on hollow mesoporous organosilica nanoparticles. This system integrates tirapazamine (TPZ), glucose oxidase (GOx), in situ-synthesized copper sulfide (CuS), and CT2A glioma cell membrane coating to enable dual tumor-targeted therapy and self-imaging capabilities. The therapeutic mechanism relies on three synergistic cascades: (1) GOx-mediated glucose oxidation to deplete oxygen and generate H2O2, establishing a self-sustaining H2O2 supply; (2) GSH-triggered CuS conversion to Cu(I), amplifying Fenton-like reactions for efficient H2O2-to-reactive oxygen species conversion and ferroptosis induction; and (3) hypoxia-activated TPZ to exert cytotoxic effects, synergizing chemotherapy with CDT. Experimental results demonstrated that HCTG-C achieves real-time MRI monitoring via GSH depletion-driven Cu valence transitions, while its self-replenishing H2O2 and oxygen-activation mechanisms significantly enhance antitumor efficacy against CT2A glioma in vitro and in vivo. By innovatively combining H2O2 self-supply cascades, hypoxia-activated chemotherapy, and ferroptosis-driven CDT, this work presents a paradigm-shifting strategy for self-imaging-guided combinatorial therapy, advancing ferroptosis-based approaches for precision glioma treatment.