Emerging drug delivery system to the brain: using extracellular vesicles and liposomes hybrid platform

Abstract Efficient drug delivery to the central nervous system (CNS) remains a major challenge because the blood-brain barrier (BBB) restricts penetration of most drugs. In this review, we summarize key principles of a unique liposome- and extracellular vesicles (EV)-based drug delivery systems for CNS, highlighting their respective advantages and limitations. Liposomes provide an FDA-approved tunable and scalable platform with established manufacturing pathways yet often face limited BBB permeability and variable targetability. EVs offer natural intercellular communication properties that may enhance biocompatibility and brain delivery in some settings. However, their translation is hindered by heterogeneity, limited control over cargo loading, source-dependent variability, and scale-up challenges. In this review, we focus on EV-liposome hybrid systems (EV-liposome) as an emerging approach designed to integrate the advantages of both liposomes and EVs. We discuss several examples of EV-liposome system designed to treat various diseases and their potential clinical applications. We also discuss the potential advantages proposed for the EV-liposome hybrid system, such as improved payload protection and enhanced BBB permeability and targeting, which have been demonstrated primarily in preclinical studies. Finally, we outline the hurdles that remain with the EV-liposome system for potential clinical applications for brain diseases, and future directions that address these hurdles and enable clinical translation of EV-liposome for brain drug delivery.