Controlled release of MSC-derived small extracellular vesicles by an injectable Diels-Alder crosslinked hyaluronic acid/PEG hydrogel for osteoarthritis improvement.

Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) show great therapeutic potential for osteoarthritis (OA). However, their low bioavailability through intraarticular injection inhibits the process of clinical application. In the present study, an injectable Diels-Alder crosslinked hyaluronic acid/PEG (DAHP) hydrogel was developed as an intraarticular delivery platform for MSC-sEVs. Our results showed that the DAHP hydrogel could be prepared easily and that its gelation properties were suitable for intraarticular administration. In vitro studies demonstrated that the DAHP hydrogel could achieve sustained release of MSC-sEVs mainly by degradation control and preserve the therapeutic functions of sEVs. An in vivo experiment revealed that the DAHP hydrogel could enhance the efficacy of MSC-sEVs for OA improvement. This study provides a suitable delivery platform for MSC-sEVs-based OA therapy. STATEMENT OF SIGNIFICANCE: Mesenchymal stem cell (MSC)-derived small extracellular vesicles (MSC-sEVs) have shown a high potential as a cell-free therapeutic factor for treating osteoarthritis (OA). The sustained release of these MSC-sEVs in the joint space is essential for their clinical application. Herein, an injectable Diels-Alder crosslinked hyaluronic acid/PEG (DAHP) hydrogel was developed for intraarticular release of MSC-sEVs. The properties of the DAHP hydrogel, namely gelation features, cytocompatibility, sustained release, and functional maintenance of MSC-sEVs, make it suitable for intraarticular injection and delivery of sEVs. The efficacy of MSC-sEVs was enhanced by the intraarticularly injected DAHP hydrogel. Our present study provides a promising sustained delivery platform for MSC-sEVs for treating OA.