BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder caused by degeneration of dopaminergic neurons and accumulation of α-synuclein protein, leading to sustained neuroinflammation. OBJECTIVE: This review analyze the application of gene silencing mediated by small interfering RNAs for α-synuclein protein and inflammatory factors in the treatment of PD. The use of exosomes-mimetic nanoparticles (EM-NPs) for siRNA delivery will be highlighted in particular. METHODS: This review highlights recent findings on the molecular mechanisms involved in PD, the development of siRNA drugs, and the potential of EM-NP-mediated siRNA delivery systems for CNS delivery. RESULTS: siRNA provides an excellent approach to silence specific disease-related genes, such as SNCA and inflammatory factors. Nevertheless, its practical application is hampered by low stability, enzymatic degradation, difficulty crossing the BBB, and non-specific activity. EM-NPs combine the advantages of biocompatibility and scalability that natural exosomes possess and synthetic nanoparticles exhibit, respectively. CONCLUSION: The delivery of siRNA molecules via EM-NPs could be considered an innovative disease-modifying approach toward treating PD patients, involving both pathological α-synuclein protein and neuroinflammation.