A Chemical Framework for Engineering Extracellular Vesicles' Biointerface to Advance Precision Therapeutics

Extracellular vesicles (EVs) are membrane-bound nanoparticles ubiquitously secreted by all cell types and serve diverse physiological and pathological functions. Due to their pivotal roles in pathophysiological processes and their inherent biomimetic properties, EVs have attracted significant attention as biomarkers, as well as for tissue engineering and drug delivery. The surface chemistry of EVs dictates their interactions with their environment. Great strides have been made to tailor this biochemical interface with the aim of enhancing cargo delivery, target specificity, immune evasion, and tracking capabilities, while preserving EVs' stability and functional integrity. Approaches to surface modification primarily encompass genetic and metabolic manipulation of parent cells, application of physical forces, and chemical reactions. In this manuscript, we introduce a comprehensive chemistry-centric framework for EV surface engineering that integrates demonstrated EV modification strategies with protein- and cell-surface chemistries not yet applied to EVs, delineating their functional scope and translational potential for advancing EV-based therapeutics.