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.