Hydrogel-mediated sustained systemic delivery of mesenchymal stem cell-derived extracellular vesicles improves hepatic regeneration in chronic liver failure.

Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have been widely reported as promising cell-free products which show therapeutics effects of the parental cells, but not their limitations. Due to the intrinsic liver tropism of MSC-EVs, they have been widely used as therapeutics or drug carriers for treatment of liver diseases. However, rapid clearance from the target site may attenuate the efficiency of systemically administered MSC-EVs. Herein, sustained release into peritoneum has been proposed as a new strategy to prolong the bioavailability of the MSC-EVs in the target liver. During intraperitoneal injection, clickable polyethylene glycol (PEG) macromeres were mixed with MSC-EVs to form EV-encapsulated PEG hydrogels via a fast, biocompatible click reaction. Upon biodegradation, the EV-laden hydrogels were swollen gradually to release EVs in a sustained manner over one month. In-vivo tracking of the labeled EVs revealed that the accumulation of EVs in the liver was extended by hydrogel-mediated delivery for one month. Four weeks after injection in rats' model of chronic liver fibrosis, the physical and histopathological investigations of the harvested liver showed superior anti-fibrosis, anti-apoptosis and regenerative effects of the EVs, when delivered by the sustained systemic release (Gel-EV) rather than the conventional bolus injection (Free-EV). Specifically, the Gel-EV system improved the anti-fibrosis, anti-inflammation, anti-apoptosis and regenerative effects of the EVs nearly to 40%, 50%, 40% and 50% compared to Free-EV, respectively, as was specified by quantification of fibrotic area, α-SMA density and caspase-3 density in the harvested tissues and ALT enzyme in serum. This study may potentiate the use of MSC-EVs as cell-free therapeutics for chronic liver failure. The sustained systemic delivery strategy may open a new paradigm to extend the effects of disease-targeting EVs over time.