# Co-Extracellular Vesicles Delivery System Enhances Immunochemotherapy for Glioblastoma

## TL;DR

A new delivery system using extracellular vesicles improves glioblastoma treatment by targeting both tumor cells and immune cells in the brain.

## Contribution

A novel co-EVs delivery system is introduced that combines macrophage-derived and drug-loaded EVs to enhance immunochemotherapy for GBM.

## Key findings

- The co-EVs system effectively crosses blood-brain barriers to target GBM cells and TAMs.
- MEVs repolarize M2 macrophages to M1, reducing the immunosuppressive environment.
- LEVDs deliver doxorubicin to GBM cells via receptor-ligand interactions, improving chemotherapy.

## Abstract

In the tumor microenvironment, both tumor cells and tumor-associated macrophages (TAMs) frequently impede the effective treatment of glioblastoma (GBM). Herein, a co-extracellular vesicles (EVs) delivery system composed of M0 RAW264.7 macrophage-derived extracellular vesicles (MEVs) and doxorubicin (DOX)-loaded lemon-derived EVs (LEVDs) is demonstrated, enabling a significant enhancement of immunochemotherapy for GBM. This system facilitates the penetration of both EV types across the blood–brain barrier and blood–brain tumor barrier, enabling precise modulation of TAMs and tumor cells within the GBM microenvironment. During this process, MEVs exhibit a remarkable homing capacity toward TAMs, and meanwhile, they are enriched in microRNA let-7f-5p, which targets the 3′ untranslated region of A20 mRNA in M2 macrophages, leading to the activation of nuclear factor κB signaling pathway. This cascade drives the repolarization of M2 macrophages toward an M1 phenotype, effectively reversing the immunosuppressive tumor microenvironment. Concurrently, LEVDs exhibit exceptional targeting of GBM cells through receptor–ligand interactions, facilitating efficient chemotherapy. As expected, the co-EVs delivery system significantly enhances immunochemotherapy for GBM through MEVs-mediated TAM repolarization and LEVDs-driven chemotherapy.