Disulfidptosis-Driven Immune-Activated Multimodal Therapy for Glioblastoma with Systemic Safety Control

Effective glioblastoma therapy requires simultaneous solutions to poor blood–brain barrier (BBB) penetration, insufficient tumor-selective killing, and treatment-related systemic toxicity. We hypothesized that a BBB-penetrating nanoplatform capable of generating distinct H2S exposures in tumor and normal tissues could enhance antitumor efficacy while mitigating doxorubicin (DOX)-induced cardiotoxicity. Here, DOX-loaded metastable molybdenum disulfide nanoflowers functionalized with an I6P8 peptide (DOX@MSI) were developed. After BBB transport and tumor accumulation, the acidic, H2O2-rich, and GSH-rich microenvironment accelerates nanoplatform degradation, promoting GSH depletion and enhanced H2S/DOX release. High local H2S upregulates xCT, while H2S/DOX-mediated mitochondrial inhibition suppresses NADPH regeneration, synergistically triggering disulfidptosis. Meanwhile, H2S suppresses the JAK2/STAT3/IDO axis, alleviating DOX-induced immunosuppression and enhancing immunogenic cell death and T-cell-mediated antitumor immunity. In contrast, slower degradation under physiological conditions enables sustained low-level H2S release, reducing the level of oxidative stress and ERK-associated apoptosis in cardiomyocytes. Together with NIR-enhanced photothermal therapy, DOX@MSI suppresses orthotopic glioblastoma while reducing cardiac injury, thereby integrating tumor-selective multimodal therapy with active organ protection.