Engineering strategies for customizing extracellular vesicle uptake in a therapeutic context

Abstract

Extracellular vesicles (EVs) are advanced therapeutic strategies that can be used to efficiently treat diseases. Promising features of EVs include their innate therapeutic properties and ability to be engineered as targeted drug delivery systems. However, regulation of EV uptake is one challenge of EV therapy that must be overcome to achieve an efficient therapeutic outcome. Numerous efforts to improve the factors that affect EV uptake include the selection of a cell source, cell cultivation procedure, extraction and purification methods, storage, and administration routes. Limitations of rapid clearance, targeted delivery, and off-targeting of EVs are current challenges that must be circumvented. EV engineering can potentially overcome these limitations and provide an ideal therapeutic use for EVs. In this paper, we intend to discuss traditional strategies and their limitations, and then review recent advances in EV engineering that can be used to customize and control EV uptake for future clinical applications.

Extracellular Vesicles and Viruses: Two Intertwined Entities

“…Finally, EVs are internalized by specific recipient cells through EV-associated transmembrane molecules, such as extracellular matrix proteins (ICAM-1, laminin, fibronectin), integrins, proteoglycans, lectins, glycolipids, phosphatidylserine (PS) and tetraspanins [ 11 ]. EV binding to recipient cells can activate cellular pathways or lead to internalization through membrane fusion, clathrin-, caveolin- or lipid raft- endocytosis, but also through phagocytosis and micropinocytosis [ 3 , 11 ]. Interestingly, the uptake of EVs by recipient cells is enhanced by EV purity, smaller size, abundance and the local environment (e.g., pH, temperature) [ 3 ].…”

“…EV binding to recipient cells can activate cellular pathways or lead to internalization through membrane fusion, clathrin-, caveolin- or lipid raft- endocytosis, but also through phagocytosis and micropinocytosis [ 3 , 11 ]. Interestingly, the uptake of EVs by recipient cells is enhanced by EV purity, smaller size, abundance and the local environment (e.g., pH, temperature) [ 3 ].…”

“…EVs are cell-secreted membrane vesicles of various sizes, compositions and origins that induce physiological changes in recipient cells through the delivery of bioactive molecules. The biomolecules contained within EVs vary depending on the tissue of origin, immune set-point and cellular context [ 3 ] and web-based compendiums such as ExoCarta [ 4 ], Vesiclepedia [ 5 ] and EVpedia [ 6 ] are now used to document the vast array of biological molecules identified in EVs of different classes [ 1 ].…”

MSC-EV therapy for bone/cartilage diseases

“…Once the key molecules necessary for therapeutic activities are identified, EVs can be engineered to contain a sufficient amount of the molecules. Artificially synthesized targeted nanoparticles that contain only the necessary molecules may be developed as the next generation cell-free therapy in the future although further elucidation of the mechanisms of EV therapy will be required ( Esmaeili et al, 2022 ; Johnson et al, 2021 ; Watson et al, 2016 ).…”

Co-aggregation of MSC/chondrocyte in a dynamic 3D culture elevates the therapeutic effect of secreted extracellular vesicles on osteoarthritis in a rat model

“…Researchers have initially tried to produce EVs with more effective therapeutic properties by selecting the proper cell source 3 . In most studies, the EVs of MSC (MSC-EVs), and in some cases chondrocyte (Cho-EVs) and chondrogenic progenitor cells have been considered for OA treatment 4 , 5 .…”