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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 \u201ccold\u201d to \u201chot\u201d 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.<\/jats:p>","DOI":"10.1021\/acsnano.6c08160","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T13:08:10Z","timestamp":1784293690000},"page":"21403-21422","source":"Crossref","is-referenced-by-count":1,"title":["A Screening-Guided\nBiomimetic Exosome-Liposome Hybrid\nNanoplatform Enables Pyroptosis-Enhanced Immune Reprogramming in Glioblastoma"],"prefix":"10.1021","volume":"20","author":[{"given":"Wang","family":"Yu","sequence":"first","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru","family":"Zhao","sequence":"additional","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liming","family":"Miao","sequence":"additional","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Bian","sequence":"additional","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Song","sequence":"additional","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2803-488X","authenticated-orcid":true,"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0194-1553","authenticated-orcid":true,"given":"Xiue","family":"Jiang","sequence":"additional","affiliation":[{"name":"Nankai University , , ,","place":["Tianjin, China, 300071"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"2026080409290210000_cit1","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/S1470-2045(09)70025-7","article-title":"Effects of Radiotherapy with Concomitant and Adjuvant\nTemozolomide Versus Radiotherapy Alone on Survival in Glioblastoma\nin a Randomised Phase Iii Study: 5-Year Analysis of the Eortc-Ncic\nTrial","volume":"10","author":"Stupp","year":"2009","journal-title":"Lancet Oncol."},{"key":"2026080409290210000_cit2","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy Plus Concomitant and Adjuvant Temozolomide for Glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N. 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