Stem cell-derived small extracellular vesicles (sEVs) have shown great therapeutic potential in tissue regeneration. However, their low production yield, undefine biological functions and low bioavailability in target tissue are critical challenges for their practical applications.
Studies have shown that biomaterials can significantly affect the paracrine effects of cells. As sEVs are the main signal carriers of intercellular paracrine communication, biomaterials are considered to affect the behaviour of sEVs. 45S5 Bioglass® (BG), as a clinically used biomaterial, has been widely used in tissue regeneration. Recently, we showed that BG ion products significantly improved production of mesenchymal stem cell MSCs-derived sEVs (MSC-sEVs). Additionally, microRNA analysis indicated that BG ion products could modulate the cargoes of MSCs-sEVs to promote their pro-angiogenesis ability.
We also used a low power and high frequency acoustic irradiation in the form of electromechanical hybrid surface-reflected bulk waves (SRBWs) to stimulate production yield of sEVs derived from human glioblastoma cells and human epithelial cells. We found that, for just 10 min stimulation followed by a short 30-min incubation period, a 1.7-fold increase in production of sEV from the cells was observed. When the cells were treated by the SRBWs for 7 cycles over 280 min, the sEV production yield increased 8-10-fold (approximately 1.7-2.1-fold/h). Increasing power can further enhance the production of sEVs. More importantly, the stimulation of SRBW only temporally reorganizes the lipid structure in the cell plasma membrane and does not generate any appreciable cavitation to induce pore formation, which is much safer for cells and maintains their viability.
To enhance the bioavailability of MSC-sEVs for treating osteoarthritis (OA) through intraarticular injection, we designed an injectable Diels-Alder crosslinked hyaluronic acid/PEG (DAHP) hydrogel as an intraarticular delivery platform for MSC-sEVs. The results showed that the DAHP hydrogel could release MSC-sEVs in a control manner by adjusting the degradation. When the hydrogels were implanted in vivo, they could enhance the efficacy of MSC-sEVs for OA improvement. We also modified embryonic stem cells derived sEVs with cyclo (Arg-Gly-Asp-D-Tyr-Lys) peptide (c(RGDyK)) to enhance their bioavailability in glioma site and loaded paclitaxel within the modified sEVs to enhance its therapeutical effects glioma.
Taken together, we use different engineering methods to enhance production yield of sEVs, modify their biological functions and increase their bioavailability in tissue. All these studies advance the applications of sEV-therapy in regenerative medicine.