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

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.