Extracellular vesicles in targeted drug delivery: from biological functions to surface engineering

Abstract Achieving precise and efficient targeting represents a major challenge in drug delivery to overcome the limitations of conventional therapies. Surface functionalization of extracellular vesicles (EVs)-nanosized membranous particles released by all cell types- has emerged as a promising strategy to enhance targeted drug delivery. EVs are naturally involved in intercellular communication by transferring bioactive molecules from donor to recipient cells, and their biologically active interface confers inherent targeting properties and a favorable safety profile, making them attractive vehicles compared to synthetic nanoparticles. However, the naїve use of EVs is often limited by nonspecific biodistribution and off-target accumulation, reducing their therapeutic efficacy. To overcome these limitations, increasing efforts have focused on engineering EVs through cargo loading and surface functionalization strategies, enabling enhanced targeting and improved delivery of therapeutic molecules. In this review, we first describe the biological features of EVs, including their biogenesis, heterogeneity, and molecular composition, which underlie their potential as drug delivery systems. We then discuss the main determinants of EV-mediated drug delivery and present current engineering strategies, including cargo loading and surface functionalization approaches, highlighting their advantages and limitations. Finally, we summarize the application of engineered EVs in the treatment of several pathological conditions, including cardiovascular, neurological, autoimmune, and cancer diseases, and discuss the major challenges in clinical translation and future perspectives for EV-based targeted therapies.