3172 - A Biomimetic Drug Delivery System by Surface-Engineered Exosomes for Glioma Dual-Mode Therapy

Purpose/Objective(s): Systemic chemotherapy for glioma faces significant challenges due to poor delivery efficiency caused by the blood-brain barrier/blood-brain tumor barrier (BBB/BBTB) and insufficient tumor penetration. While exosomes show promise as natural drug carriers with inherent biocompatibility, low immunogenicity, and BBB-crossing capabilities, current nanoparticle-mediated systems require synergistic therapeutic strategies to achieve tumor-specific accumulation and controlled drug release.

Materials/Methods: We developed a bioengineered exosome system through a donor cell-assisted membrane modification strategy. Sulfhydrylated exosomes were dual-functionalized with RGD peptide (targeting tumor neovasculature integrins) and folic acid (FA, enhancing tumor cellular uptake) to create GD-FA-Exos. Doxorubicin-loaded gold nanorods (AuNRs) with pH-sensitive properties (pH-sensitive DNs) were incorporated into exosomes. This design enables 1) dual-ligand mediated tumor targeting, 2) pH-responsive drug release in acidic tumor microenvironment, and 3) NIR-triggered hyperthermia therapy.

Results: The engineered exosomes demonstrated 2.3-fold higher tumor accumulation compared to single-ligand systems through RGD/FA synergistic targeting. pH-sensitive DNs showed 78% drug release at tumor pH (5.5) versus 22% at physiological pH (7.4). NIR irradiation (808 nm) induced localized hyperthermia (T = 42.1°C) that simultaneously triggered burst drug release (89% within 2 h) and achieved photothermal ablation. This dual-mode therapy resulted in tumor growth inhibition in orthotopic glioma models with minimal systemic toxicity.

Conclusion: Our biomimetic system overcomes multiple biological barriers through rational integration of active targeting, environmental responsiveness, and external controllability. The dual-mode therapy combining chemo-photothermal effects significantly improves therapeutic efficacy while reducing off-target damage. This engineering paradigm establishes a versatile platform for personalized glioma treatment, with potential clinical translation prospects for overcoming drug resistance and preventing tumor recurrence. The successful integration of biological carriers with synthetic nanomaterials opens new avenues for developing next-generation brain-targeted delivery systems.