Surface engineering of extracellular vesicles: trends, strategies, and applications in diagnosis and therapy

Extracellular vesicles (EVs) have emerged as pivotal mediators of intercellular communication, offering exceptional biocompatibility and an innate ability to cross biological barriers. These properties make them highly attractive for therapeutic and diagnostic applications. Despite this potential, unmodified EVs face clinical limitations including nonspecific targeting and rapid clearance. Surface engineering strategies, which encompass physical, chemical, and genetic approaches, are being developed to address these challenges. These techniques enhance tissue specificity, prolonging circulation time, and allow for the integration of multifunctional capabilities. Furthermore, hybrid techniques that combine these methods are yielding advanced "smart EVs" that can respond to specific microenvironmental cues. Such engineered EVs facilitate real-time tracking through integrated fluorescent probes and enable precision drug delivery, with promising applications in oncology, neurology, cardiovascular diseases, and so on. Recent innovations leverage modular platforms that integrate microfluidics and computational modeling to optimize the functionalization of EVs for uses in tumor immunotherapy, regenerative therapies, etc. However, the clinical translation of these technologies remains hindered by inherent EV heterogeneity, inefficiencies in isolation, and scalability limitations. Advanced manufacturing technologies, including tangential flow filtration and AI-driven analytics, show considerable promise for standardizing production and improving reproducibility. This review synthesizes cutting-edge surface modification strategies, evaluates their diagnostic and therapeutic impacts, and outlines interdisciplinary solutions designed to overcome existing translational barriers. By harmonizing engineering precision with biological fidelity, surface-functionalized EVs hold transformative potential for next-generation theragnostic and personalized medicine.