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

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.