Co-Extracellular Vesicles Delivery System Enhances Immunochemotherapy for Glioblastoma.

Area of Science:

• Oncology
• Nanomedicine
• Immunotherapy

Background:

• Glioblastoma (GBM) treatment is hindered by tumor cells and immunosuppressive tumor microenvironment (TME) mediated by tumor-associated macrophages (TAMs).
• Effective delivery across the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) remains a significant challenge for GBM therapies.

Purpose of the Study:

• To develop a co-extracellular vesicle (EV) delivery system for enhanced glioblastoma (GBM) immunochemotherapy.
• To investigate the synergistic effects of macrophage-derived EVs (MEVs) and doxorubicin-loaded lemon-derived EVs (LEVDs) in modulating TAMs and targeting GBM cells.

Main Methods:

• Engineered M0 macrophage-derived EVs (MEVs) enriched with microRNA let-7f-5p for TAM repolarization.
• Doxorubicin (DOX)-loaded lemon-derived EVs (LEVDs) for targeted chemotherapy delivery.
• Evaluation of the co-EV system's ability to cross the BBB/BBTB and its efficacy in GBM treatment.

Main Results:

• MEVs demonstrated homing to TAMs and facilitated M2 to M1 repolarization via let-7f-5p targeting of A20 mRNA, activating NF-κB signaling and reversing immunosuppression.
• LEVDs efficiently targeted GBM cells through receptor-ligand interactions, enabling effective chemotherapy.
• The co-EV system significantly enhanced GBM immunochemotherapy efficacy through combined TAM repolarization and chemotherapy.

Conclusions:

• The co-EV delivery system represents a promising strategy for overcoming GBM treatment resistance.
• This approach effectively reprograms the immunosuppressive TME and delivers targeted chemotherapy, offering a new avenue for GBM therapy.