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bioRxiv · 10.64898/2026.11.02.760854

Cascaded Dual-Targeting (WTW/TAT) Liposomes Delivery DOX for Precision Glioblastoma Treatment

Li, X.·Gao, X.·Wang, J.·Liao, X.·Huang, Z.·Yin, G.
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Abstract

Glioblastoma (GBM) remains difficult to treat because the blood-brain barrier (BBB) and blood-tumor barrier (BTB) severely limit drug transport into tumor tissue. To address these delivery constraints, we developed a dual-targeted liposomal nanoplatform (WT-LIP) that integrates a WTW dual-targeting peptide to promote receptor-mediated BBB transcytosis and specificity to GBM and a TAT peptide to enhance post-barrier penetration and tumor-cell uptake, enabling sequential barrier crossing and GBM targeting. DOX@WT-LIP efficiently encapsulated doxorubicin (DOX) and increased endothelial transport in vitro, achieving a permeated dose of 60.74 {+/-} 2.14% at 480 min, while producing deeper transendothelial penetration and greater downstream tumor killing in a BBB/GBM co-culture. In orthotopic U251-luc models, DiD-labeled WT-LIP showed enhanced brain/tumor accumulation (G/B = 2.16 {+/-} 0.06), and DOX@WT-LIP markedly suppressed tumor growth (74.92% inhibition), improved survival, and exhibited comparatively reduced systemic toxicity. This work highlights a ligand-guided strategy that couples efficient BBB transport with tumor-selective delivery to improve GBM chemotherapy.

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Li, X., Gao, X., Wang, J., Liao, X., Huang, Z., Yin, G.. 2026-11-04. Cascaded Dual-Targeting (WTW/TAT) Liposomes Delivery DOX for Precision Glioblastoma Treatment. https://doi.org/10.64898/2026.11.02.760854

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