Cell-derived nanovesicle-mediated drug delivery to the brain: Principles and strategies for vesicle engineering

Developing strategies toward safe and effective drug delivery into the central nervous system (CNS) with improved targeting abilities and reduced off-target effects is crucial. CNS-targeted drug carriers made of synthetic molecules raise concerns about their biodegradation, clearance, immune responses, and neurotoxicity. Cell-derived nanovesicles (CDNs) have recently been applied in CNS-targeted drug delivery, because of their intrinsic stability, biocompatibility, inherent homing capability, and the ability to penetrate through biological barriers, including the blood-brain barrier. Among these CDNs, extracellular vesicles and exosomes are the most studied because their surface can be engineered and modified to cater to brain targeting. In this review, we focus on the application of CDNs in brain-targeted drug delivery to treat neurological diseases. We cover recently developed methods of exosome derivation and engineering, including exosome-like particles, hybrid exosomes, exosome-associated adeno-associated viruses, and envelope protein nanocages. Finally, we discuss the limitations and project the future development of the CDN-based brain-targeted delivery systems, and conclude that engineered CDNs hold great potential in the treatment of neurological diseases.