The landscape of extracellular vesicles combined with intranasal delivery towards brain diseases

Extracellular vesicles (EVs), natural nano-vesicles carrying multiple bioactive molecules, have been broadly applied in brain diseases due to their excellent biocompatibility, low immunogenicity, and superior physicochemical properties. However, owing to the complexity of the blood-brain barrier (BBB) and brain diseases, and under the common oral and injectable drug delivery, EVs still have poor brain delivery and retention capabilities, and cannot achieve clinical therapeutic effects. Intranasal (IN) delivery may be a potential way to address this issue. IN delivery can bypass the body circulation and BBB, and enter the brain directly through the nasal mucosa, which offers the advantages of painless, non-invasive, and repeated administration. Herein, we discuss recent developments in the therapy of brain diseases with IN-delivered EVs. We outline the basic properties of EVs and summarize the effects of EVs on the brain. We then discuss the mechanistic pathways and advantages of IN delivery of EVs and review studies that combine EVs with IN delivery for the treatment of brain diseases. Finally, we briefly outline the challenges and prospects for IN-delivered EVs and suggest possible recommendations to facilitate the clinical translation and development of IN-delivered EVs.