Sustained and Localized Delivery of Mesenchymal Stem Cells-Derived Extracellular Vesicles by an In Situ Forming Click...

Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) hold great promise as a cell-free therapy for diabetic nephropathy (DN), but their therapeutic efficacy is limited by rapid clearance from the target site after bolus injection. Herein, an in situ-forming biodegradable hydrogel has been developed for sustained and localized release of EVs into the renal subcapsular space. The MSC-EVs were encapsulated within a synthetic hydrogel based on poly(ethylene glycol) (PEG) during a click reaction between thiol and vinyl sulfone end groups of four-arm PEG macromers at the site of injection in the kidney capsule of DN-modeled mice. The MSC-EV-laden PEG hydrogel gradually swelled and released EVs in a sustained manner over one month. The DN mice treated with the EV-delivering hydrogel exhibited further improved renal function with attenuated histopathological damage, reduced proinflammatory cytokine levels, and lower tubular cell apoptosis compared with the DN mice treated with free EVs. Specifically, the hydrogel-mediated delivery of MSC-EVs could significantly enhance antifibrotic effects of MSC-EVs and even prevent and reverse the progression of renal fibrosis in a DN mouse model, an event that was not observed by the free EV treatment. Collectively, this prolonged delivery system may open a new paradigm for improved EV therapies for various chronic diseases.