State-of-the-art surface engineering of stem cell-derived small extracellular vesicles for targeted tissue delivery: strategies and clinical practice

Engineering the surface of small extracellular vesicles (sEVs) derived from stem cells is a strategy for displaying proteins, targeting ligands such as peptides or antibodies, or other functional molecules on the vesicle membrane to improve tissue- and cell-specific delivery. These modifications can be achieved through several approaches, including genetic engineering of parental cells, chemical functionalization of membrane lipids or proteins, membrane anchor-based display systems, and therapeutic cargo loading to enhance delivery efficiency to diseased sites. Surface-engineered stem cell-derived sEVs have shown considerable promise for the treatment of cancer, neurological disorders, inflammatory conditions, and tissue injury because they combine the intrinsic biological advantages of stem cell-derived vesicles with improved targeting precision. This review summarizes recent advances in the surface engineering of stem cell-derived sEVs for tissue-targeted drug delivery, with emphasis on genetic, chemical, and anchor-mediated modification strategies, targeting ligands, and controlled release approaches that improve therapeutic specificity and efficacy. The review also discusses emerging translational opportunities and current challenges related to the clinical application of surface-engineered stem cell-derived sEVs.