Exosomal <scp>TGM2</scp> From Hypoxia‐Primed Olfactory Mucosa <scp>MSCs</scp> Attenuates Senescent Astrocytes via <scp>NRF1</scp> / <scp>TFAM</scp> Signaling in Parkinson's Disease

ABSTRACT Parkinson's disease (PD) progression is closely linked to astrocyte senescence and mitochondrial dysfunction. Olfactory mucosa mesenchymal stem cells (OM‐MSCs)‐derived exosomes (OM‐MSC‐Exos) have emerged as promising therapeutic vectors for neurodegenerative disorders. However, it remains unclear whether OM‐MSC‐Exos can alleviate astrocyte senescence in PD by restoring mitochondrial function through the nuclear respiratory factor 1 (NRF1)‐mitochondrial transcription factor A (TFAM) pathway. We employed a 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced PD mouse model, a 1‐methyl‐4‐phenylpyridinium (MPP)‐induced astrocyte senescence model, molecular analysis, and targeted knockdown to investigate the mechanism of normoxia‐ or hypoxia‐preconditioned OM‐MSC‐Exos (N‐Exos/H‐Exos) against astrocyte senescence. The motor coordination ability of mice was evaluated using the rotarod, hanging, and pole tests. In the MPTP‐induced PD mouse model, both OM‐MSCs and OM‐MSC‐Exos increased the number of tyrosine hydroxylase‐positive neurons in the substantia nigra pars compacta, delayed astrocyte senescence, and improved motor function. H‐Exos showed better efficacy than normoxia controls. In vitro experiments confirmed that H‐Exos reduced the number of senescence‐associated β‐galactosidase‐positive astrocytes, reversed mitochondrial membrane potential decline and mitochondrial reactive oxygen species upregulation, and mitigated mitochondrial DNA leakage in MPP‐induced senescent and naturally aged astrocytes. Venn analysis screened transglutaminase 2 (TGM2) as the key exosomal cargo linking PD, senescence, and NRF1. TGM2 was enriched in H‐Exos, and H‐Exos treatment restored the down‐regulated TGM2 levels in astrocytes and up‐regulated NRF1/TFAM. Knocking down TGM2 significantly weakened the neuroprotective and anti‐senescence effects of H‐Exos. In conclusion, H‐Exos could mitigate senescence‐dependent PD pathology, an effect associated with the TGM2 enrichment in exosomes and activation of the NRF1‐TFAM axis in astrocytes.