Extracellular vesicles (EVs) are naturally secreted, non-nuclear lipid nanostructures by biological sources with intrinsic features such as biocompatibility, low immunogenicity, and the ability to bypass biological barriers. Despite the growing interest in EV research, their biological potential as a versatile drug delivery vehicle has yet to be widely translated for clinical use. Fewer than 3 % of clinical trials involving these cell-free vesicles have utilized them for drug delivery applications. This review elucidates the reasons behind the translational gap through a comprehensive analysis of pharmacokinetic and tissue transport challenges faced by EVs across various tissue barriers, including the cartilage, blood-brain interface, ocular, gastrointestinal, and skin tissues, and summarizes their endogenous roles within these tissue microenvironments. The review also delves into key engineering design principles, presenting a portfolio of both tissue-specific and tissue-independent targeting strategies to overcome tissue barriers and enhance the precise delivery of engineered EVs. A comprehensive comparison of key factors – such as biodistribution, cellular uptake, intracellular fate, and safety profile – between EVs and benchmark synthetic platforms is also provided to guide the selection of optimal carrier designs for diverse tissue targets and further highlights the steps needed to bridge translational gaps of engineered EVs from a clinical perspective. In conclusion, the review underscores the significance of engineered EVs as a promising next-generation nanocarrier for precision nanomedicine, offering an alternative to conventional synthetic platforms.