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

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.