miR-23a-3p-abundant small extracellular vesicles released from Gelma/nanoclay hydrogel for cartilage regeneration.

Articular cartilage has limited self-regenerative capacity and the therapeutic methods for cartilage defects are still dissatisfactory in clinic. Recent studies showed that exosomes derived from mesenchymal stem cells promoted chondrogenesis by delivering bioactive substances to the recipient cells, indicating exosomes might be a novel method for repairing cartilage defect. Herein, we investigated the role and mechanism of human umbilical cord mesenchymal stem cells derived small extracellular vesicles (hUC-MSCs-sEVs) on cartilage regeneration. In vitro results showed that hUC-MSCs-sEVs promoted the migration, proliferation and differentiation of chondrocytes and human bone marrow mesenchymal stem cells (hBMSCs). MiRNA microarray showed that miR-23a-3p was the most highly expressed among the various miRNAs contained in hUC-MSCs-sEVs. Our data revealed that hUC-MSCs-sEVs promoted cartilage regeneration by transferring miR-23a-3p to suppress the level of PTEN and elevate expression of AKT. Moreover, we fabricated Gelatin methacrylate (Gelma)/nanoclay hydrogel (Gel-nano) for sustained release of sEVs, which was biocompatible and exhibited excellent mechanical property. In vivo results showed that hUC-MSCs-sEVs containing Gelma/nanoclay hydrogel (Gel-nano-sEVs) effectively promoted cartilage regeneration. These results indicated that Gel-nano-sEVs have a promising capacity to stimulate chondrogenesis and heal cartilage defects, and also provided valuable data for understanding the role and mechanism of hUC-MSCs-sEVs in cartilage regeneration.