Mesenchymal Stem Cell-Derived Extracellular Vesicles for Functional Intracellular Delivery: Engineering, Targeting, Cellular Uptake, Biological Barriers, and Therapeutic Translation

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are considered promising biological carriers for biomolecule and drug delivery because of their inherent biological activities, biocompatibility, and capacity to carry a variety of therapeutic cargoes. However, the limited cargo-loading capacity of native EVs, their inefficient delivery to target cells, intracellular trafficking barriers, and limitations in the functional release of their cargo restrict their therapeutic applications. EV engineering encompasses a range of approaches to overcome these limitations, including donor cell modification, endogenous cargo loading and active sorting mechanisms, post-isolation loading methods, surface engineering, and EV–lipid-based hybrid systems. In this review, engineered MSC-EVs are evaluated in terms of cargo loading, targeting, cellular uptake, intracellular trafficking, and functional cargo delivery. We also compare the loading strategies used for nucleic acids, proteins, enzymes, and small molecules, in terms of their advantages, their limitations, and their effect on EV biological activity. The therapeutic applications of MSC-EV-based systems in cardiovascular diseases, wound healing, neurological and musculoskeletal disorders, inflammatory diseases, and cancer are evaluated. The central conclusion of this review is that the therapeutic efficacy of MSC-EVs depends not only on the amount of cargo delivered but also on its delivery to the appropriate target cells, intracellular targeting, and preservation of its biological activity. Accordingly, future EV engineering strategies should aim to simultaneously improve cargo loading, disease-specific targeting, local retention, and cargo stability. Progress on these four fronts is what would make MSC-EVs predictable enough for clinical use.