Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (10): 4989-4999.doi: 10.4103/NRR.NRR-D-25-00404

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Engineered mesenchymal stem cell–derived extracellular vesicles overexpressing miR-146a alleviate neuroinflammation in Alzheimer’s disease

Jia Zhang1, 2, #, Siqi He1, 2, #, Qiguo Xiao1, #, Weijie Jiang1, Bo Wang3, 4, Jing Lu1, Hongfeng Gu3, Yajin Liao1, Zhi Wang1, Ying Xu5, Dan Wang6, *, Xiaoqing Tang1, 3, *, Ling Qi2, *   

  1. 1The Second Affiliated Hospital, University of South China, Hengyang, Hunan Province, China; 
    2Division of Gastroenterology, Institute of Digestive Disease, the Affiliated Qingyuan Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong Province, China; 
    3Department of Physiology & Key Laboratory of Hunan Province for Major Brain Diseases, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China; 
    4The First Affiliated Hospital, Institute of Anesthesiology, University of South China, Hengyang, Hunan Province, China; 
    5Guangdong-Hong Kong-Macau Institute of Central Nervous System Regeneration, Key Laboratory of Central Nervous System Regeneration, Ministry of Education, Jinan University, Guangzhou, Guangdong Province, China; 
    6Department of pathology, Beihua University, Jilin, Jilin Province, China

  • Online:2026-10-15 Published:2026-06-15
  • Contact: Dan Wang, PhD, jljl1215@163.com; Xiaoqing Tang, PhD, tangxq-usc@usc.edu.cn; Ling Qi, PhD, qiling1718@gzhmu.edu.cn.
  • Supported by:
    This work was supported by the Natural Science Foundation of Hunan Province, Nos. 2025JJ81006 (to JZ), 2025JJ90150 (to QX), 2022JJ30522 (to QX), 2022JJ70034 (to ZW); Clinical Medical Technology Innovation Guidance Project of Hunan Province, No. 2021SK51813 (to BW).

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Abstract: Alzheimer’s disease is an inflammatory neurodegenerative disease for which no effective clinical treatment currently exists. We have previously reported that mesenchymal stem cell–derived extracellular vesicles delay retinal degeneration by exerting anti-inflammatory effects though the miR-146a–nuclear receptor subfamily 4 group A member 3 axis; however, it remains unclear how NR4A3 drives inflammation. Herein, we engineered mesenchymal stem cell–derived extracellular vesicles overexpressing miR-146a to explore their possible neuroprotective effects and the underlying mechanisms in both cell and animal models of Alzheimer’s disease. In HT22 cells co-cultured with lipopolysaccharide-induced RAW264.7/BV2 cells, extracellular vesicles overexpressing miR-146a significantly reduced the number of apoptotic cells and inhibited proinflammatory cytokine expression, nuclear factor (NF)-κB activation, and caspase-3/apoptosis regulator BAX signaling. These effects of extracellular vesicles overexpressing miR-146a were replicated in 5×FAD mice. In addition, extracellular vesicles overexpressing miR-146a inhibited the activation of microglia and astrocytes, reduced amyloid-β and phosphorylated tau expression, lowered the number of apoptotic cells in the hippocampus, and improved the cognitive function of these Alzheimer’s disease model mice. Mechanistically, miR-146a negatively regulated the expression of nuclear receptor subfamily 4 group A member 3 and suppressed the expression of proinflammatory cytokines and nuclear factor-κB signaling. Furthermore, NR4A3 overexpression promoted nuclear factor-κB and proinflammatory cytokine expression as well as nuclear factor-κB signaling. The upregulation of NR4A3 and the inflammatory response was reversed by miR-146a overexpression. Finally, NR4A3 was identified as a transcriptional activator of nuclear factor-κB using chromatin immunoprecipitation polymerase chain reaction. Collectively, these findings indicate that extracellular vesicles overexpressing miR-146a may alleviate the progression of Alzheimer’s disease by exerting anti-inflammatory effects via the NR4A3–nuclear factor-κB axis. They are thus a potential therapeutic candidate for the clinical treatment of neurodegenerative diseases.

Key words: Alzheimer’s disease, amyloid-β, cognitive function, mesenchymal stem cell–derived extracellular vesicles, microglia, miR-146a, neuroinflammation, neuroprotection, nuclear factor-κB, nuclear receptor subfamily 4 group A member 3 (NR4A3)