Engineering the Future: Strategic Advances in Extracellular Vesicle-Mediated Drug Delivery Systems.

Extracellular vesicles (EVs) are lipid bilayer-enclosed nanoparticles naturally secreted by cells that inherently lack replicative capacity and function as endogenous carriers of biological cargo including proteins, nucleic acids, and metabolites for intercellular communication. Leveraging their intrinsic biocompatibility and biomimetic transport properties, EVs have emerged as versatile drug delivery platforms with distinct therapeutic advantages. Recent advancements have developed two precision-engineered derivatives: structurally and cargo-modified engineered EVs, and EV mimetics integrating synthetic nanomaterials. Both types are designed to enhance targeting specificity and therapeutic efficacy, yet their strong intercorrelations frequently cause confusion. This review systematically examines the evolving landscape of EV-based delivery systems by establishing conceptual distinctions between native EVs, engineered EVs, and EV mimetics, while comparatively analyzing their preparation methodologies, clinical translation progress, and performance characteristics as drug carriers. Through systematic discussion of clinical challenges, including safety, clinical feasibility, and cross-laboratory reproducibility, we propose optimization directions integrating artificial intelligence with drug delivery systems, thereby providing insights and methodologies for next-generation EV-inspired therapeutic delivery platforms.