Biomimetic extracellular vesicles derived from chimeric antigen receptor monocytes to treat glioblastoma: An efficient and safe intranasal drug delivery nanoplatform

Abstract

Background: Extracellular vesicles (EVs) have emerged as a promising pharmacotherapeutic modality for glioblastoma (GBM) drug delivery. However, the clinical translation of EVs remains restricted due to their low yield and demanding extraction steps. Therefore, extracellular vesicle mimetics (EVMs), as alternatives to EVs, have received much attention. Results: Herein, inspired by the inherent GBM tropism of monocytes and the editable target recognition ability of chimeric antigen receptors (CARs), we present the synthesis and systemic evaluation of a doxorubicin (DOX)-loaded nanoplatform (termed CAR-EVMs@DOX) generated by loading DOX into EVMs derived from CAR-modified monocytes (CAR-EVMs) via a modified extrusion method. Due to insufficient GBM drug delivery efficacy and great systemic toxicity caused by the resistance of the blood−brain barrier (BBB), CAR-EVMs@DOX can be administered intranasally to bypass the BBB, resulting in dramatic GBM-targeted migration and accumulation in the GBM site. Moreover, compared with intravenous administration, intranasal delivery of CAR-EVMs@DOX increases tumor inhibition efficacy while protecting against DOX-induced cardiotoxicity. Conclusions: The findings of our study demonstrate that the intranasal administration of the facile and well-designed nanoplatform CAR-EVMs@DOX is an advanced drug delivery tactic for GBM therapy, with the potential for future clinical translation.

Keywords

• Extracellular vesicle mimetics
• Chimeric antigen receptors
• Membrane extrusion
• Intranasal administration
• Glioblastoma