Mesenchymal stem cell–derived small extracellular vesicles promote mitochondrial repair of dopaminergic neurons via Homer protein homolog 3 in Parkinson's disease

Parkinson's disease is a major neurodegenerative disorder, and mitochondrial dysfunction has been increasingly recognized as a key contributor to its pathogenesis. Recent studies suggest that treatment with mesenchymal stem cell–derived small extracellular vesicles offers a promising cell-free strategy for mitigating neurodegeneration. In the present study, we investigated the effects of induced pluripotent stem cell–derived mesenchymal stem cell–derived small extracellular vesicles on dopaminergic neurons in a murine Parkinson's disease model and explored the underlying mechanisms related to mitochondrial impairment. A Parkinson's disease mouse model was established using 1-methyl-4-phenyl-1,2,4,5- tetrahydropyridine-induced neurotoxicity, followed by the intranasal administration of mesenchymal stem cell–derived small extracellular vesicles and comprehensive behavioral and pathological assessments. To elucidate the mechanistic basis of any effects, we examined mitochondrial function and Homer protein homolog 3 (Homer3) expression in brain tissue. Mice with Homer3 knockdown were used to validate the role of Homer3 in the therapeutic effects of mesenchymal stem cell–derived small extracellular vesicles. Mesenchymal stem cell–derived small extracellular vesicle administration significantly reduced motor dysfunction in 1-methyl-4-phenyl-1,2,4,5-tetrahydropyridine-induced Parkinson's disease mice by protecting dopaminergic neurons. Furthermore, mesenchymal stem cell–derived small extracellular vesicles increased both mitochondrial number and function through Homer3 upregulation in Parkinson's disease mice. The therapeutic benefits of mesenchymal stem cell–derived small extracellular vesicles in rescuing dopaminergic neurons were impaired by Homer3 knockdown. Collectively, these findings suggest that, at least in part, mesenchymal stem cell–derived small extracellular vesicles ameliorate dopaminergic neuron damage via the Homer3-mediated restoration of mitochondrial function in a mouse model of Parkinson's disease. Our results highlight the neuroprotective role of mesenchymal stem cell- derived small extracellular vesicles in Parkinson's disease and provide new perspectives on their therapeutic potential.