Authors
Wang Yu, Ru Zhao, Liming Miao, Jie Bian, Yiyao Zhou, Xiaoyu Zhao, Wei Song, Yue Wang, Xiue Jiang
Published in
ACS nano. Jul 17, 2026. Epub Jul 17, 2026.
Abstract
Glioblastoma (GBM) is a highly lethal brain tumor, with therapeutic efforts hampered by the restrictive blood-brain barrier (BBB) and a profoundly immunosuppressive tumor microenvironment (TME). Driven by bioinformatics analysis identifying epidermal growth factor receptor (EGFR) and caspase-3 as key regulators of an immune-evasive pyroptosis pathway, we screened natural compounds and identified quercetin (Q) and chlorogenic acid (C) as dual-targeting agents, thereby laying a therapeutic foundation for amplifying pyroptosis in GBM treatment. The compounds were conjugated into a glutathione-responsive prodrug (QSSC) and encapsulated in a tumor-derived exosome-liposome nanoplatform (QSSC@Exo-LNP), enabling enhanced BBB penetration and intracranial targeting. Mechanistic studies revealed a dual-pathway amplification of pyroptosis, in which C directly activates caspase-8 to initiate gasdermin E (GSDME)-mediated pyroptosis, while Q/C-mediated EGFR inhibition activates mitochondrial pro-apoptotic protein, thereby augmenting caspase-3 and intensifying pyroptotic cell death. Upon intravenous injection, QSSC@Exo-LNP triggers robust pyroptosis, releasing DAMPs and tumor antigens for immune activation and macrophage reprogramming, converting the TME from "cold" to "hot" state. Moreover, this treatment strategy can significantly inhibit the distant tumors in the primary-distal orthotopic GBM model. This study proposes a strategy for the precise immunotherapy of GBM by exploiting natural products to target overexpressed GSDME and induce the pyroptotic cascade.
PMID:
42466899
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 1
- Comments 0