Engineering MSC-Derived Small Extracellular Vesicles for Targeted Cargo Delivery to the Injured Spinal Cord

Mesenchymal stromal/stem cell-derived small extracellular vesicles (MSC-sEVs) improve locomotor outcomes in preclinical models of spinal cord injury (SCI). After systemic administration, however, most of the MSC-sEVs are taken up by the liver, spleen and lungs, so only a small fraction reaches the injured cord; the vesicle surface and contents are determined by an unmodified parent cell, so both recipient cell engagement and cargo delivery remain heterogeneous rather than specified. Surface engineering and cargo loading may address these limitations. Because targeting and cargo determine the outcome together in vivo, the two are treated here as one framework. The extent to which these strategies have been combined in MSC-sEVs has not been established. This review identifies which MSC-sEVs tested in the injured cord display an engineered ligand, which carry a deliberately loaded cargo, and which do both. A target × cargo × engineering method matrix records the model and carrier of each entry. It shows that an engineered ligand has been paired with a deliberately loaded cargo in two studies on an MSC-sEV tested in SCI, but that neither reports the ligand density per particle or the delivered fraction of the dose, so the contribution of the combination remains unmeasured.