Extracellular vesicles (EVs), such as microvesicles and exosomes, are membranous structures containing bioactive material released by several cells types, including mesenchymal stem/stromal cells (MSCs). Increasing lines of evidences point to EVs as paracrine mediators of the beneficial effects on tissue remodeling associated with cell therapy. Administration of MSCs-derived EVs has therefore the potential to open new and safer therapeutic avenues, alternative to cell-based approaches, for degenerative diseases. However, an enhanced knowledge about in vivo EVs trafficking upon delivery is required before effective clinical translation. Only a few studies have focused on the biodistribution analysis of exogenously administered MSCs-derived EVs. Nevertheless, current strategies for in vivo tracking in animal models have provided valuable insights on the biodistribution upon systemic delivery of EVs isolated from several cellular sources, indicating in liver, spleen, and lungs the preferential target organs. Different strategies for targeting EVs to specific tissues to enhance their therapeutic efficacy and reduce possible off-target effects have been investigated. Here, in the context of a possible clinical application of MSC-derived EVs for tissue regeneration, researchers from the Regina Elena National Cancer Institute review the existing strategies for in vivo tracking and targeting of EVs isolated from different cellular sources and the studies elucidating the biodistribution of exogenously administered EVs.
Schematic representation of different methods to promote tissue- or cell-type-specific
targeting of extracellular vesicles (EVs)
EVs can be targeted to particular cellular receptor either by modifications of EVs-producing cells (red squares) or modification of EVs after secretion (yellow squares). In the first case, EVs-producing cells can be modified: expressing ligands, peptides, or viral-derived envelop proteins in the outer portion of a transmembrane protein; loading cells with iron oxide particles to allow for magnetic targeting. Alternatively, secreted EVs can be modified linking cell-specific peptides to the EVs surface via association with polyethylene glycol (PEG) polymer chains or by EVs-liposome fusion. Click chemistry can be used to modify both EVs-producing cells and purified EVs.