Cellular Uptake of Engineered Extracellular Vesicles: Biomechanisms, Engineered Strategies, and Disease Treatment

Extracellular vesicles (EVs), lipid-enclosed nanosized membrane vesicles, are regarded as new vehicles and therapeutic agents in intercellular communication. During internal circulation, if EVs are not effectively taken up by recipient cells, they will be cleared as "cellular waste" and unable to deliver therapeutic components. It can be seen that cells uptake EVs are the prerequisite premise for sharing intercellular biological information. However, natural EVs have a low rate of absorption by their recipient cells, off-target delivery, and rapid clearance from circulation, which seriously reduces the utilization rate. Affecting the uptake rate of EVs through engineering technologies is essential for therapeutic applications. Engineering strategies for customizing EV uptake can potentially overcome these limitations and enable desirable therapeutic uses of EVs. In this review, the mechanism and influencing factors of natural EV uptake will be described in detail. Targeting each EV uptake mechanism, the strategies of engineered EVs and their application in diseases will be emphatically discussed. Finally, the future challenges and perspectives of engineered EVs are presented multidimensionally. This review thoroughly explores the mechanisms of extracellular vesicle (EV) uptake and highlights various engineering strategies for enhancing EV uptake, backed by experimental evidence. It emphasizes the importance of improving the uptake rate of EVs, introduces the potential application of engineered EVs in clinical treatment, and offers suggestions for future research directions.image