# Engineered Small Extracellular Vesicles Targeting Tumor‐Associated Endothelial Cells to Effectively Remodel the Glioma Microenvironment

## TL;DR

This study introduces a new drug delivery system using modified vesicles to target brain tumors, effectively delivering drugs and boosting immune responses.

## Contribution

A novel delivery platform using IGFBP7-modified sEVs to target glioma-associated endothelial cells and deliver therapeutics across the blood-brain barrier.

## Key findings

- IGFBP7-sEVs efficiently delivered temozolomide to gliomas at low doses, inhibiting tumor growth.
- STING agonist-loaded IGFBP7-sEVs outperformed direct injection, remodeling the tumor microenvironment and enhancing immune cell function.
- Endothelial-restricted STING activation reduced CD8+ T cell exhaustion and amplified anti-tumor immunity.

## Abstract

Owing to the existence of the blood–brain barrier (BBB), achieving high‐efficacy, tumor‐selective delivery of therapeutic agents continues to be a pivotal unmet need in the treatment of glioblastoma. Here, based on the finding that CD93 is exclusively up‐regulated on glioma‐associated vascular endothelial cells (VECs), small extracellular vesicles (sEVs) were modified with insulin‐like growth factor‐binding protein 7 (IGFBP7), a natural ligand of CD93, to create a delivery platform that can deliver therapeutic agents to glioma‐associated VECs with high efficiency. At markedly reduced intravenous doses, IGFBP7‐sEVs efficiently concentrated temozolomide (TMZ) within glioma and elicited pronounced tumor growth inhibition. More strikingly, systemic administration of stimulator of interferon genes (STING) agonist‐loaded IGFBP7‐sEVs outperformed direct intratumoral injection of free STING agonist: the glioma microenvironment (GME) was extensively remodeled and antigen‐presenting capacity of myeloid cells was markedly enhanced. Moreover, endothelial‐restricted STING activation attenuated the exhaustion of CD8+ T cells. Consequently, the intensity of the tumor‐specific immune response was markedly augmented. Our data suggest that IGFBP7‐modified sEVs represent a novel platform that enables highly efficient, glioma VECs‐targeted delivery of therapeutics into glioma, and are adaptable to a broad spectrum of agents, especially immunomodulators. It is a novel and effective strategy for treating gliomas.

This study developed a novel drug delivery platform that overcomes the blood‐brain barrier in glioblastoma. By fusing IGFBP7 with small extracellular vesicles, the platform specifically targets tumor vasculature. It effectively delivers temozolomide, suppressing tumor growth at low doses. Moreover, when loaded with immune agonists, it remodels the tumor microenvironment and activates robust anti‐tumor immunity, presenting an innovative and versatile strategy for glioma therapy.