Crosstalk between exosomes and cellular senescence: A core vicious loop promoting α-synuclein pathology in Parkinson’s disease

Abstract

Parkinson’s disease is characterized by α-synuclein aggregation, dopaminergic neuron loss, and neuroinflammation. Emerging evidence reveals complex crosstalk between exosomes and cellular senescence in Parkinson’s disease pathogenesis. Exosomes mediate α-synuclein transmission and neuroinflammation, while delivering protective factors such as miRNAs that inhibit cellular senescence. Senescent cells secrete pro-inflammatory factors via mitochondrial dysfunction and the senescence-associated secretory phenotype, linking to Parkinson’s disease mitophagy defects. This forms a vicious “senescence-protein deposition-inflammation” cycle, with senescent cell-derived exosomes exacerbating α-synuclein aggregation and inflammation. Therapeutically, exosomes are ideal drug carriers due to blood–brain barrier penetrability and low immunogenicity for targeted antioxidant delivery. Future perspectives highlight exosome-based biomarkers and brain-gut axis intervention as promising directions. We propose integrating exosome engineering and senolytic strategies to lay the foundation for early diagnosis and precision therapy of Parkinson’s disease, promoting diagnosis-intervention translational research and bridging bench-tobedside translation.