Bioengineering of extracellular vesicles with scaffold proteins for drug delivery

Extracellular vesicles (EVs) play a crucial role in intercellular communication by transmitting information and participate in various physiological and pathological processes, including cancer, neurodegenerative diseases, and cardiovascular diseases. EVs have emerged as promising drug delivery vehicles, possessing unique advantages such as low immunogenicity, the ability to cross biological barriers, and a versatile cargo capacity. However, it still faces multiple challenges such as low production yield, limited targeting ability, and the complexity of using engineered EVs for clinical applications. Scaffold proteins (such as tetraspanins (TSPANs) and type I transmembrane proteins) can enhance the targeting specificity, loading capacity and stability of engineered EVs. Engineering with these proteins enables EVs to be directed to specific tissues for efficient drug delivery. Scaffold protein-based engineering of EVs has enabled the loading of various types of cargo, such as proteins, nucleic acids, and gene editors, and their targeted delivery to specific organs, such as heart and brain. It is expected to revolutionize drug delivery systems in the future and change the treatment methods for many diseases. This article reviews in detail the research progress of reported scaffold proteins and their engineered EVs by classification. We conduct a comprehensive analysis of scaffold proteins and their applications. Lastly, we discuss the current challenges and propose future directions of scaffold protein-based EV engineering.