Selecting Administration Routes for Therapeutic Extracellular Vesicles to Achieve Optimal Drug Delivery

Extracellular vesicles (EVs) have emerged as promising therapeutic carriers owing to their biocompatibility, low immunogenicity, and ability to transport diverse biological cargo. However, successful EV-based therapy depends not only on carrier engineering but also on selecting an administration route appropriate for the target disease. This review examines major administration routes for therapeutic EVs, with lipid nanoparticles (LNPs) as a comparative platform, and discusses how anatomical barriers, biodistribution, clearance, inflammatory microenvironments, and target-cell localization influence delivery efficiency. Systemic administration provides broad accessibility but often results in substantial off-target distribution, whereas localized or barrier-bypassing routes can enhance exposure at specific pathological sites. Importantly, anatomical proximity does not necessarily guarantee efficient delivery, highlighting the need for quantitative assessment of target-tissue bioavailability. We propose a shift from a carrier-centered toward a disease- and route-centered paradigm integrating disease pathology, anatomical accessibility, biodistribution, and carrier engineering.