Authors
Anna C Debski, Catherine M Gorick, Victoria R Breza, Jackson Tirrell, Krishan Perumal, Katherine M Nowak, Ji Song, Natasha D Sheybani, Richard J Price
Published in
Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e76997. Aug 05, 2026. Epub Aug 05, 2026.
Abstract
The blood-brain and blood-tumor barriers impede therapeutic delivery to glioblastoma (GBM). Furthermore, dysfunctional endothelial cells in GBM enable an immunosuppressive tumor microenvironment (TME) and enhance therapeutic resistance. However, the significance of endothelial dysfunction for GBM progression also positions the endothelium as a rich target for gene therapy. Here, we leveraged the presence of exofacial thiols (SH) on cells within the TME and developed polymeric, plasmid-bearing, densely PEGylated, polyethyleneimine nanoparticles (NPs) functionalized with free thiol groups to facilitate targeting and transfection (SH-NPs). Delivering SH-NPs to GBM with focused ultrasound (FUS) elicited exceptionally high tropism for GBM endothelium (>70% efficiency), significantly surpassing that achieved via convection-enhanced delivery (CED). "Sonoselective," endothelial cell-specific, transfection was then achieved by incorporating the CD144 promoter. Using this system, we delivered a CXCL9 plasmid to GBM endothelium. This intervention enhanced CD8+ effector and CD4+ helper T cell representation in the TME and significantly improved responsiveness of the tumor to aPD1 checkpoint inhibition. Broadly considered, this sonoselective non-viral transfection platform may be adapted to multiple therapeutic strategies. Further, the approach holds an advantage over AAVs with tropism for brain endothelial cells due to the ability of FUS to provide locoregional targeting specifically to brain tumor endothelium.
PMID:
42555202
Bibliographic data and abstract were imported from PubMed on 06 Aug 2026.
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