Synergistic Dual-Targeting Bacterial Extracellular Vesicles Delivering Paclitaxel for Precision Glioblastoma Therapy.

Abstract

Glioblastoma (GBM) poses significant therapeutic challenges due to the restrictive blood-brain barrier (BBB) and blood-tumor barrier (BTB). To overcome these obstacles, we developed a dual-targeted nanodelivery system (AT-BEVs) based on engineered bacterial extracellular vesicles (BEVs). By integrating Angiopep-2 for LRP-1-mediated BBB transport and TAT peptide for enhanced tumor penetration, AT-BEVs achieve sequential barrier and tumor targeting. This platform effectively encapsulates hydrophobic chemotherapeutics such as paclitaxel (PTX) and enables tumor microenvironment-responsive drug release. In orthotopic GBM models, AT-BEVs loaded with PTX (AT-BEVs@PTX) showed improved brain tumor accumulation, inhibited tumor progression, and significantly extended survival. Our work presents a promising strategy to overcome dual delivery barriers in GBM and offers translational potential for targeted cancer therapy.