摘要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 5xFAD 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.