Hit the bull's eye: Engineered extracellular vesicles for targeted therapy

Extracellular vesicles (EVs) are nanoscale vesicles secreted by most cell types and have a similar composition to their parent cells. By delivering effector molecules, EVs serve as mediators of intercellular communication and hold significant therapeutic potential. However, challenges such as uncertain in vivo biodistribution and the risk of adverse reactions in non-target tissues still limit their broader clinical translation. Recent studies increasingly demonstrate that EVs can be engineered to target pathological tissues, thereby enhancing their specificity and therapeutic efficacy across various diseases. This review first outlines the biogenesis, composition, trafficking, cellular uptake, and biological functions of EVs, followed by a description of their natural biodistribution patterns, emphasizing how molecular heterogeneity contributes to natural targeting. We then discuss engineering strategies for EV targeting, comparing their advantages, limitations, and industrial feasibility. Subsequently, we examine how organ-specific microenvironment influences targeting efficiency of engineered EVs and summarize their applications in targeted therapy across various organs and tissues. Finally, the major challenges and future directions for the clinical translation of engineered EVs in targeted therapy are highlighted.