Wharton's jelly mesenchymal stem cell-derived small extracellular vesicles as natural nanoparticles to attenuate cartilage injury via microRNA regulation

It's of great priority to exploit alternative solutions which can avoid the risks of mesenchymal stem cells and synthetic nanomaterials. Here, we identified the property of Wharton's jelly MSC-derived small extracellular vesicles as nanomaterials and evaluated their effects in osteoarthritis. It is demonstrated that the native nanotherapeutic agent has great potential for simultaneously repairing cartilage and subchondral bone. sEV-microRNAs-involved biocircuits make significant contributions to treatment of OA. [Display omitted] •WJMSC-sEVs is an ideal cell-free nanotherapeutic agent in treating osteoarthritis;•WJMSC-sEVs has dual protective effects on cartilage and subchondral bone;•miRNA profiles of WJMSC-sEVs may induce cartilage repair by regulating Calcium signaling pathway, ECM-receptor interaction pathway and NOTCH signaling pathway. The main strategy of tissue repair and regeneration focuses on the application of mesenchymal stem cells and cell-based nanoparticles, but there are still multiple challenges that may have negative impacts on human safety and therapeutic efficacy. Cell-free nanotechnology can effectively overcome these obstacles and limitations. Mesenchymal stem cell (MSC)-derived natural small extracellular vesicles (sEVs) represent ideal nanotherapeutics due to their low immunogenicity and lack of tumorigenicity. Here, sEVs harvested from Wharton’s jelly mesenchymal stem cells (WJMSCs) were identified. In vitro results showed that WJMSC-sEVs efficiently entered chondrocytes in the osteoarthritis (OA) model, further promoted chondrocyte migration and proliferation and modulated immune reactivity. In vivo, WJMSC-sEVs notably promoted chondrogenesis, which was consistent with the effect of WJMSCs. RNA sequencing results revealed that sEV-microRNA-regulated biocircuits can significantly contribute to the treatment of OA, such as by promoting the activation of the calcium signaling pathway, ECM-receptor interaction pathway and NOTCH signaling pathway. In particular, let-7e-5p, which is found in WJMSC-sEVs, was shown to be a potential core molecule for promoting cartilage regeneration by regulating the levels of STAT3 and IGF1R. Our findings suggest that WJMSC-sEV-induced chondrogenesis is a promising innovative and feasible cell-free nanotherapy for OA treatment.