Abstract <p>While mammalian-derived extracellular vesicles (EVs) face significant challenges in clinical translation due to scalability, cost, and safety, plant-derived EVs (PDEVs) have emerged as a promising alternative. This review focuses on EVs derived from hemp (<i>Cannabis sativa</i> L.), or HEVs, a particularly compelling source that combines the general benefits of PDEVs, such as improved safety and scalability, with a unique, inherent therapeutic cargo. HEVs are naturally enriched with a potent mix of cannabinoids, terpenes, and flavonoids, which may enhance therapeutic outcomes through synergistic interactions—a phenomenon known as the ‘entourage effect.’ Preclinical studies already demonstrate their potential, showing significant anti-cancer effects against aggressive tumors like glioblastoma, along with neuroprotective and anti-inflammatory properties. However, the critical challenge hindering their clinical application is the lack of standardized, GMP (Good Manufacturing Practice)-compliant manufacturing protocols to address the inherent biochemical variability of the source material. Overcoming these obstacles will be vital to unlocking the potential of HEVs as a novel, scalable frontier in nanomedicine.</p> Graphical Abstract <p></p>