Redirecting Monocyte Differentiation With Engineered Extracellular Vesicles for Glioma Immunotherapy

ABSTRACT

During glioma progression, monocytes abundantly infiltrate but primarily differentiate into immunosuppressive macrophages to promote tumor growth. Redirecting monocyte differentiation offers a compelling yet underexplored therapeutic opportunity. In this work, we found M1‐polarized macrophage‐derived extracellular vesicles (M1‐EVs) efficiently induced monocytes to differentiate into anti‐tumor macrophages via tumor necrosis factor alpha (TNF‐α)‐mediated signaling. Despite promising, the therapeutic efficacy of M1‐EVs was constrained by insufficient glioma accumulation and CD47‐mediated phagocytic inhibition. To address this challenge, we further engineered M1‐EVs with dual‐targeting specificity by genetically incorporating a tumor‐directed chimeric antigen receptor (CAR) against IL13Rα2 or EGFRvIII together with CD47‐blocking SIRPα variants. The resulting dual‐targeting EVs (M1‐CS‐EVs) exhibited enhanced blood‐brain barrier (BBB) penetration and glioma accumulation while locally disrupting CD47‐SIRPα interactions. In three orthotopic glioma models, M1‐CS‐EVs elicited a potent anti‐tumor immune response and enhanced tumor phagocytosis, significantly suppressing tumor growth while prolonging animal survival. Our findings establish a platform technology for directing monocyte differentiation toward anti‐tumor phenotypes, offering a broadly applicable strategy for glioma treatment.