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Background  Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have been shown to have therapeutic potential for ischemic diseases and are considered an alternative to cell therapy. However, the low retention and poor stability of EVs post-transplantation in vivo remain obstacle prior to the clinical application of EVs.    Methods  This study was designed to investigate whether collagen matrix could increase the retention and stability of EVs and further improve the therapeutic effects in murine acute kidney injury (AKI) model. EVs were isolated from human placental MSCs (hP-MSC-EVs) and encapsulated in a collagen matrix. Then, we investigated whether collagen matrix can prolong the retention of EVs in vivo, further enhancing the therapeutic efficiency of EVs in AKI.    Results  Our results indicated that collagen matrix could effectively encapsulate EVs, significantly increase the stability of EVs, and promote the sustained release of EVs. Collagen matrix has improved the retention of EVs in the AKI model, which was proved by  Gaussia  luciferase (Gluc) imaging. The application of collagen matrix remarkably facilitated the proliferation of renal tubular epithelial cells in AKI compared with EVs alone. Moreover, collagen matrix could further augment the therapeutic effects of hP-MSC-EVs as revealed by angiogenesis, fibrosis and apoptosis, and functional analysis. Finally, we found that EVs play a therapeutic role by inhibiting endoplasmic reticulum (ER) stress.    Conclusions  Collagen matrix markedly enhanced the retention of EVs and further augmented the therapeutic effects of EVs for AKI. This strategy for improving the efficacy of EVs therapy provides a new direction for cell-free therapy.

Enhanced therapeutic effects of MSC-derived extracellular vesicles with an injectable collagen matrix for experimental acute kidney injury treatment