Exploring the potential of plasma and adipose mesenchymal stem cell-derived extracellular vesicles as novel platforms for neuroinflammation therapy

Rummenigge Oliveira Silva; Mohamed Haddad; Hermine Counil; Charlotte Zaouter; Shunmoogum A Patten; Tamas Fulop; Charles Ramassamy

doi:10.1016/j.jconrel.2024.11.060

Exploring the potential of plasma and adipose mesenchymal stem cell-derived extracellular vesicles as novel platforms for neuroinflammation therapy

J Control Release. 2024 Dec 7:377:880-898. doi: 10.1016/j.jconrel.2024.11.060. Online ahead of print.

Authors

Rummenigge Oliveira Silva¹, Mohamed Haddad¹, Hermine Counil¹, Charlotte Zaouter¹, Shunmoogum A Patten¹, Tamas Fulop², Charles Ramassamy³

Affiliations

¹ INRS, Centre Armand-Frappier Santé Biotechnologie, 531 Boul des Prairies, Laval, QC H7V 1B7, Canada.
² Research Center on Aging, Faculty of Medicine and Health Sciences, University Sherbrooke, Sherbrooke, QC J1H 4N4, Canada.
³ INRS, Centre Armand-Frappier Santé Biotechnologie, 531 Boul des Prairies, Laval, QC H7V 1B7, Canada. Electronic address: charles.ramassamy@iaf.inrs.ca.

PMID: 39617173
DOI: 10.1016/j.jconrel.2024.11.060

Abstract

Persistent reactive oxygen species (ROS) and neuroinflammation contribute to the onset and progression of neurodegenerative diseases, underscoring the need for targeted therapeutic strategies to mitigate these effects. Extracellular vesicles (EVs) show promise in drug delivery due to their biocompatibility, ability to cross biological barriers, and specific interactions with cell and tissue receptors. In this study, we demonstrated that human plasma-derived EVs (pEVs) exhibit higher brain-targeting specificity, while adipose-derived mesenchymal stem cells EVs (ADMSC-EVs) offer regenerative and immunomodulatory properties. We further investigated the potential of these EVs as therapeutic carriers for brain-targeted drug delivery, using Donepezil (DNZ) as the model drug. DNZ, a cholinesterase inhibitor commonly used for Alzheimer's disease (AD), also has neuroprotective and anti-inflammatory properties. The size of EVs used ranged from 50 to 300 nm with a surface charge below -30 mV. Both formulations showed rapid cellular internalization, without toxicity, and the ability to cross the blood-brain barrier (BBB) in a zebrafish model. The have analyzed the anti-inflammatory and antioxidant actions of pEVs-DNZ and ADMSC-EVs-DNZ in the presence of lipopolysaccharide (LPS). ADMSC-EVs significantly reduced the inflammatory mediators released by HMC3 microglial cells while treatment with pEVs-DNZ and ADMSC-EVs-DNZ lowered both phagocytic activity and ROS levels in these cells. In vivo experiments using zebrafish larvae revealed that both EV formulations reduced microglial proliferation and exhibited antioxidant effects. Overall, this study highlights the potential of EVs loaded with DNZ as a novel approach for treating neuroinflammation underlying various neurodegenerative diseases.

Keywords: Adipose mesenchymal stem cell-derived extracellular vesicles; Donepezil; Drug delivery; Neuroinflammation; Plasma-derived extracellular vesicles; Reactive oxygen species.