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A Screening-Guided Biomimetic Exosome-Liposome Hybrid Nanoplatform Enables Pyroptosis-Enhanced Immune Reprogramming
Wang Yu1, Ru Zhao1, Liming Miao1
1Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin300071, China.
ACS Nano
|July 17, 2026
Summary
This study developed a novel nanoplatform delivering natural compounds to enhance pyroptosis, a cell death pathway, for treating glioblastoma (GBM). This approach overcomes the blood-brain barrier and reprograms the tumor microenvironment for effective immunotherapy.
Area of Science:
- Oncology
- Immunology
- Nanomedicine
Background:
- Glioblastoma (GBM) presents significant therapeutic challenges due to the blood-brain barrier (BBB) and an immunosuppressive tumor microenvironment (TME).
- Pyroptosis, a pro-inflammatory cell death pathway, is often evaded by GBM, limiting treatment efficacy.
- Bioinformatics identified epidermal growth factor receptor (EGFR) and caspase-3 as key regulators in GBM's immune-evasive pyroptosis.
Purpose of the Study:
- To develop a novel therapeutic strategy for GBM by amplifying pyroptosis using natural compounds.
- To create a targeted nanodelivery system for enhanced BBB penetration and intracranial delivery.
- To investigate the dual-pathway amplification of pyroptosis and its immunomodulatory effects in GBM.
Main Methods:
- Screening of natural compounds led to the identification of quercetin (Q) and chlorogenic acid (C).
- Compounds were conjugated into a glutathione-responsive prodrug (QSSC) and encapsulated in a tumor-derived exosome-liposome nanoplatform (QSSC@Exo-LNP).
- Mechanistic studies elucidated the dual-pathway pyroptosis amplification involving caspase-8, GSDME, EGFR inhibition, and caspase-3.
Main Results:
- QSSC@Exo-LNP demonstrated enhanced BBB penetration and intracranial targeting.
- The treatment triggered robust pyroptosis, releasing damage-associated molecular patterns (DAMPs) and tumor antigens.
- This induced immune activation, reprogrammed macrophages, and converted the TME from 'cold' to 'hot', significantly inhibiting primary and distant tumors.
Conclusions:
- The developed QSSC@Exo-LNP nanoplatform effectively amplifies pyroptosis in GBM.
- This strategy overcomes GBM-specific challenges like the BBB and immunosuppression.
- The study presents a promising approach for GBM immunotherapy by inducing pyroptosis and immune responses.
