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.