Intranasal Delivery of Extracellular Vesicles Derived from Human Bone Marrow Mesenchymal Stem Cells Dampens Neuroinflammation and Ameliorates Motor Deficits in a Mouse Model of Cortical Stroke

Authors

Saviana Antonella Barbati
Chiara D'Amelio
Chiara Feroleto
Marta Morotti
Ida Nifo Sarrapochiello
Francesca Natale
Domenica Donatella Li Puma
Yolanda Gomez-Galvez, Thomas Jefferson UniversityFollow
Elena Blanco-Suarez, Thomas Jefferson UniversityFollow
Lorraine Iacovitti, Thomas Jefferson UniversityFollow
Lucia Leone
Salvatore Fusco
Maria Vittoria Podda
Claudio Grassi

Document Type

Article

Publication Date

11-3-2025

Comments

This article is the author's final published version in Experimental Neurology, Volume 396, February 2026, Article 115540.

The published version is available at https://doi.org/10.1016/j.expneurol.2025.115540. Copyright © 2025 The Authors.

Abstract

Early treatment of ischemic stroke can significantly reduce disability and mortality rates. Stem cell-derived extracellular vesicles (EVs) have shown potential as therapeutics for neurological disorders. This study explored whether intranasal administration of EVs from human bone marrow mesenchymal stem cells (BM-MSCs) enhances forelimb motor function recovery in a mouse model of motor cortex stroke and investigated their mechanism of action, focusing on neuroinflammation. C57BL/6JRj mice received EV treatment of 0.1 × 10⁹ EVs per dose per day, 48 h post-stroke and twice weekly for four weeks. EV-treated mice showed significant improvement in forelimb deficits, as evaluated using a series of motor tests. Histopathological assessments revealed reduced infarct volume and decreased astrogliosis and microglial activation in EV-treated mice. EV treatment led to changes in microglial morphology in the peri-infarct area, associated with increased anti-inflammatory cytokines interleukin (IL)-10 and IL-13 and decreased pro-inflammatory cytokines IL-1β, IL-6, and tumor necrosis factor-alpha. Reduced expression of nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome and Cleaved Caspase-1 following EV treatment supports their role in dampening inflammation. In vitro experiments using oxygen-glucose deprivation confirmed that EVs attenuated the inflammatory phenotype of microglia and reduced neuronal apoptosis. EV cargo analysis revealed neuroprotective molecules, including anti-inflammatory cytokines and brain-derived neurotrophic factor (BDNF), which may contribute to their immunomodulatory properties. These findings show that EVs mitigate post-stroke brain immune response, promoting tissue healing and recovery. Our comprehensive characterization of the effects of human BM-MSC-derived EVs, encompassing functional, tissue, cellular, and molecular aspects, underscores their therapeutic potential and supports their use in stroke treatment. © 2025 The Authors

Recommended Citation

Barbati, Saviana Antonella; D'Amelio, Chiara; Feroleto, Chiara; Morotti, Marta; Nifo Sarrapochiello, Ida; Natale, Francesca; Puma, Domenica Donatella Li; Gomez-Galvez, Yolanda; Blanco-Suarez, Elena; Iacovitti, Lorraine; Leone, Lucia; Fusco, Salvatore; Podda, Maria Vittoria; and Grassi, Claudio, "Intranasal Delivery of Extracellular Vesicles Derived from Human Bone Marrow Mesenchymal Stem Cells Dampens Neuroinflammation and Ameliorates Motor Deficits in a Mouse Model of Cortical Stroke" (2025). Department of Neuroscience Faculty Papers. Paper 93.
https://jdc.jefferson.edu/department_neuroscience/93

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Language

English