Authors
Meng Zhang, Chenteng Lin, Khishigjargal Ganbat, Wei Meng, Heemin Kang, Wenjia Gao, Hongyuan Li, Guangwei Jiang, Sharon Prince, Cyrille Boyer, Xinjun Wang, Yi Wang, Rongqin Huang
Published in
ACS nano. Volume 20. Issue 44. Pages 29387-29401. Nov 10, 2026.
Abstract
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.
PMID:
43007758
Bibliographic data and abstract were imported from PubMed on 11 Nov 2026.
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