Extracellular vesicles from inflammatory-primed stromal cells reduce in vitro inflammation in Sandhoff disease model.

Authors

Nikolia Darzenta, Emily Davis, Rie Watanabe, Melikasadat Mollabashi, Savanie Fernando, Maria C Naskou

Published in

Scientific reports. Jul 11, 2026. Epub Jul 11, 2026.

Abstract

Sandhoff disease (SD) is a fatal lysosomal storage disorder caused by β-N-acetylhexosaminidase deficiency, resulting in GM2 ganglioside accumulation, severe neurodegeneration, and chronic neuroinflammation. While enzyme-restoring therapies, such as AAV gene transfer, effectively target the primary enzymatic deficit, neuroinflammation persists and contributes to disease progression, motivating the development of anti-inflammatory adjuncts alongside disease-modifying interventions. Extracellular vesicles released by mesenchymal stromal cells (MSC-EVs) are acellular lipid nanoparticles that contain immunomodulatory molecules and can cross physical barriers, without immunogenicity issues. These features make MSC-EVs promising candidates for anti-inflammatory therapeutics targeting neuropathology. The anti-inflammatory potency of MSC-EVs is increased by priming parent MSCs with pro-inflammatory cytokines, resulting in IFEVs, as referred to in this study. Here, we evaluated the in vitro anti-inflammatory effects of IFEVs in a feline model of SD. IFEVs reduced SD neuroinflammation, lowering IL-6, TNF-α, and IL-1β protein levels in SD neuronal-mixed glia, with concordant transcriptional downregulation of NF-κB/p65 and NLRP3 components and upregulation of arginase 1 mRNA after 48 h of treatment. In SD peripheral blood mononuclear cells, IFEVs significantly increased the proportion of regulatory T cells and the Treg/T-effector cell ratio without inducing cytotoxicity. Together, these findings demonstrate that IFEVs reduced neuroinflammation and altered blood-circulating T-cell populations in an in vitro SD model, supporting their further preclinical development as a complementary immunomodulatory therapy for SD.

PMID:
42436308
Bibliographic data and abstract were imported from PubMed on 12 Jul 2026.

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