Advanced engineering strategies of extracellular vesicles for enhanced central nervous system regeneration and disease modulation

The limited regenerative capacity of the central nervous system (CNS) following injury or disease requires the development of novel therapeutic strategies to promote endogenous repair. Extracellular vesicles (EVs) have emerged as a promising cell-free therapeutic that naturally encapsulates bioactive paracrine factors responsible for tissue repair. Achieving optimal therapeutic outcomes with EVs requires rational engineering to improve their delivery, targeting, and efficacy. Here, we present a comprehensive overview of the recent advacements in EV engineering. To improve their capacity to bypass biological barriers and enhance therapeutic effectiveness, key strategies such as surface ligand functionalization, therapeutic drug loading, and cellular preconditioning are used. We then explore the application of these engineered EVs in treating major CNS pathologies, including traumatic brain and spinal cord injuries (TBIs and SCIs), glioma, stroke, and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Finally, we discuss current challenges in accelerating the clinical translation of engineered EVs as next-generation therapeutics for CNS disorders.