Extracellular vesicles: cargo loading, degradation and secretory pathways, and their intersection with autophagy

Extracellular vesicles (EVs) are secreted by nearly all cell types and fulfil a crucial role in intercellular communication by transporting diverse cargo, including enzymes, mRNA, growth factors, chemokines, and cytokines. Although EVs were initially thought to primarily function in waste elimination, it is now clear that they can be diverted from degradation and instead actively secreted to mediate intercellular communication. While the processes of EV biogenesis, degradation, and release have been extensively studied, many aspects remain poorly understood. The involvement of molecular pathways shared by EV biogenesis and autophagy-a lysosome-mediated disposal mechanism-suggests the existence of common regulatory controls. Despite the partial overlap in molecular machineries involved in cargo sorting, the mechanisms that balance the degradation and secretory pathways of EVs, as well as their interplay with autophagy, remain elusive. This review discusses the molecular machinery that dictates the selective cargo loading into EVs. Additionally, it examines the coordination between degradation and secretory pathways in EV biology and situates these processes within the broader context of autophagy. The substantial overlap in molecular pathways, shared proteins, and complementary mechanisms suggests a high degree of coordination between these systems.