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bioRxiv · 10.64898/2026.01.12.698945

Mesenchymal stem cell-extracellular vesicles deliver microRNAs that prevent nerve growth factor-induced sensory neuron sensitization

Qiu, L.·Rois, P.-M.·Muslu-Ufuk, T.·Price, J. L.·Cloake, A.·Miska, E. A.·Williams, T. L.·Smith, E. S. J.
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Abstract

Osteoarthritis (OA) affects 600 million individuals globally, pain being a hallmark symptom. Emerging clinical evidence supports the use of mesenchymal stem cells (MSCs) and their extracellular vesicles (MSC-EVs) for pain relief in knee OA. In mice, MSC-EVs ameliorate OA-induced pain and normalize knee-innervating neuron excitability. Moreover, it has been shown that overnight incubation of sensory neurons with MSC-EVs prevents the OA-associated mediator nerve growth factor (NGF) sensitizing sensory neurons. Here, we found that protease-mediated MSC-EV shaving inhibited MSC-EV internalization into sensory neurons and the ability of MSC-EVs to prevent NGF-induced sensitization. In addition, acute, 10-minute, exposure of sensory neurons to MSC-EVs was also insufficient to counteract NGF. We hypothesized that MSC-EVs trigger transcriptional changes and found that inhibiting transcription prevented NGF-induced sensitization. MicroRNAs (miRNAs) can be delivered to cells by MSC-EVs, and certain miRNAs regulate transcription and pain; small RNA-sequencing of our MSC-EVs identified three candidate miRNAs, miR-21-5p, miR-148a-3p and miR-451a. Using gold nanoparticle delivery, each miRNA was able to prevent NGF sensitization of sensory neurons, a combination of all three showing the most pronounced effect. These findings demonstrate that MSC-EVs prevent NGF-induced sensory neuron sensitization via cellular uptake and transcriptional regulation that is mediated by miRNAs.

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Qiu, L., Rois, P.-M., Muslu-Ufuk, T., Price, J. L., Cloake, A., Miska, E. A., Williams, T. L., Smith, E. S. J.. 2026-01-12. Mesenchymal stem cell-extracellular vesicles deliver microRNAs that prevent nerve growth factor-induced sensory neuron sensitization. https://doi.org/10.64898/2026.01.12.698945

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