Hydrogel-Mediated Sustained Systemic Delivery of Mesenchymal Stem Cell-Derived Extracellular Vesicles Improves Hepatic Regeneration in Chronic Liver Failure
Abstract
Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have been widely reported as promising cell-free products that show therapeutic 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 the 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 1 month. In vivo tracking of the labeled EVs revealed that the accumulation of EVs in the liver was extended by hydrogel-mediated delivery for 1 month. Four weeks after injection in a rat model of chronic liver fibrosis, the physical and histopathological investigations of the harvested liver showed superior antifibrosis, anti-apoptosis, and regenerative effects of the EVs when delivered by the sustained systemic release (Gel-EV) to the conventional bolus injection (Free-EV). Specifically, the Gel-EV system improved the antifibrosis, anti-inflammation, anti-apoptosis, and regenerative effects of the EVs to nearly 40, 50, 40, and 50% compared to Free-EV, respectively, as was specified by quantification of the 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.
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Bioengineering or using biomaterials such as hydrogels to deliver EVs may be a potential improvement measure.
“Bioengineering or using biomaterials such as hydrogels to deliver EVs may be a potential improvement measure [198, 259].”
From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [259]
In rat models of fibrosis, hydrogel-mediated delivery extended the accumulation of MSC-EVs in livers for one month and showed superior regenerative, anti-apoptosis, and anti-fibrosis effects.
“In rat models of fibrosis, hydrogel-mediated delivery extended the accumulation of MSC-EVs in livers for one month and showed superior regenerative, anti-apoptosis, and anti-fibrosis effects [259].”
From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [259]
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“Bioengineering or using biomaterials such as hydrogels to deliver EVs may be a potential improvement measure [198, 259].”
- Authors
- Mardpour, S., Ghanian, M. H., Sadeghi-abandansari, H., Mardpour, S., Nazari, A., Shekari, F., & Baharvand, H.
- Affiliations
- Iran University of Medical Sciences (IR)
- Royan Institute (IR)
- Department of Cancer Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Isar 11, 47138-18983 Babol, Iran.
- University of Science and Culture (IR)
- Corresponding author
- Baharvand, Hossein
- Venue
- ACS Applied Materials & Interfaces
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-09-17
- Volume
- 11
- Issue
- 41
- Pages
- 37421-37433
- ISSN
- 1944-8244 (ISSN-L)
- 1944-8252
- OpenAlex
- W2974626482
- Cited by
- 211
- References
- 4
- Citations by year
- 2026: 25 · 2025: 23 · 2024: 40 · 2023: 37 · 2022: 29 · 2021: 37 · 2020: 20
- FWCI
- 7.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- ACS Applied Materials & Interfaces (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Royan Institute
- National Institute for Medical Research Development
- Ministry of Health and Medical Education
- Iran Science Elites Federation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- mesenchymal stem cell-derived extracellular vesicles, hydrogel drug delivery, sustained drug release, intraperitoneal injection, poly(ethylene glycol) hydrogels, click chemistry, chronic liver fibrosis, liver regeneration, cell-free therapy, liver tropism, anti-fibrosis, apoptosis inhibition, anti-inflammation
- MeSH terms
- Extracellular Vesicles, Animals, Disease Models, Animal, Humans, Liver Regeneration, Male, Polyethylene Glycols, Rats, Wistar, Rats, End Stage Liver Disease, Mesenchymal Stem Cells
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