Engineered Microglia Potentiate the Action of Drugs against Glioma Through Extracellular Vesicles and Tunneling Nanotubes

Abstract

Gliomas remain difficult to treat because of their metastatic and recurrent nature and the existence of the blood-brain barrier (BBB), which impedes drug delivery. Microglia, the resident macrophages in the CNS, can be recruited by gliomas and can penetrate the tumor. In this study, microglia (BV2 cells) are used as transport vectors to deliver paclitaxel for the treatment of glioma. To avoid paclitaxel toxicity in microglia, liposomes are first employed to isolate the drug from BV2 cells. Dipalmitoyl phosphatidylserine (DPPS), as an "eat me" signal, is doped into liposomes to amplify their phagocytosis by microglia. This study demonstrates that engineered microglia can cross the BBB, independently migrate toward gliomas, and transfer cargo to glioma cells. Of note, extracellular vesicles and tunneling nanotubes are found to offer unique modes of cargo transportation between microglia and glioma cells. In vivo, the engineered drug-loaded microglia has a high ability to target the brain, penetrate glioma, and suppress tumor progression, supporting the notion that the use of engineered microglia is a potential strategy for the treatment of glioma. These findings present new opportunities for exploration into the use of microglia as transport vectors to deliver therapeutic agents through specific membrane nanotubes and vesicles.