Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC-EVs) have been recognized as a promising cell-free therapy for acute kidney injury (AKI), which avoids safety concerns associated with direct cell engraftment. However, low stability and retention of MSC-EVs have limited their therapeutic efficacy. RGD (Arg-Gly-Asp) peptide binds strongly to integrins, which have been identified on the surface of MSC-EV membranes; yet RGD has not been applied to EV scaffolds to enhance and prolong bioavailability. Here, we developed RGD hydrogels, which we hypothesized could augment MSC-EV efficacy in the treatment of AKI models. In vivo tracking of the labeled EVs revealed that RGD hydrogels increased retention and stability of EVs. Integrin gene knockdown experiments confirmed that EV−hydrogel interaction was mediated by RGD−integrin binding. Upon intrarenal injection into mouse AKI models, EV-RGD hydrogels provided superior rescuing effects to renal function, attenuated histopathological damage, decreased tubular injury, and promoted cell proliferation in early phases of AKI. RGD hydrogels also augmented antifibrotic effects of MSC-EVs in chronic stages. Further analysis revealed that the presence of microRNA let-7a-5p in MSC-EVs served as the mechanism contributing to the reduced cell apoptosis and elevated cell autophagy in AKI. In conclusion, RGD hydrogels facilitated MSC-derived let-7a-5p-containing EVs, improving reparative potential against AKI. This study developed an RGD scaffold to increase the EV integrin-mediated loading and in turn improved therapeutic efficacy in renal repair; therefore this strategy shed light on MSC-EV application as a cell-free treatment for potentiated efficiency.

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For large segmental bone defects, porous titanium scaffolds have some advantages, however, they lack electrical activity which hinders their further use. In this study, a barium titanate (BaTiO 3 ) piezoelectric ceramic was used to modify the surface of a porous Ti6Al4V scaffold (pTi), which was characterized by scanning electron microscopy, energy dispersive spectroscopy, X-ray photoelectron spectroscopy, and roughness and water contact angle analyses. Low intensity pulsed ultrasound (LIPUS) was applied in vitro and in vivo study. The activity of bone marrow mesenchymal stem cells, including adhesion, proliferation, and gene expression, was significantly superior in the BaTiO 3 /pTi, pTi + LIPUS, and BaTiO 3 /pTi + LIPUS groups than in the pTi group. The activity was also higher in the BaTiO 3 /pTi + LIPUS group than in the BaTiO 3 /pTi and pTi + LIPUS groups. Additionally, micro-computed tomography, the mineral apposition rate, histomorphology, and the peak pull-out load showed that these scaffold conditions significantly enhanced osteogenesis and osseointegration 6 and 12 weeks after implantation in large segmental bone defects in the radius of rabbits compared with those resulting from the pTi condition. Consequently, the improved osteogenesis and osseointegration make the BaTiO 3 /pTi + LIPUS a promising method to promote bone regeneration in large segmental bone defects for clinical application.