The α-
synuclein aggregates are the main component of Lewy bodies in
Parkinson's disease (PD) brain, and they showed
immunotherapy could be employed to alleviate α-
synuclein aggregate pathology in PD. Recently we have generated
DNA aptamers that specifically recognize α-
synuclein. In this study, we further investigated the in vivo effect of these aptamers on the neuropathological deficits associated with PD. For efficient delivery of the aptamers into the mouse brain, we employed modified exosomes with the neuron-specific
rabies viral
glycoprotein (
RVG) peptide on the membrane surface. We demonstrated that the aptamers were efficiently packaged into the RVG-exosomes and delivered into neurons in vitro and in vivo. Functionally, the aptamer-loaded RVG-exosomes significantly reduced the α-
synuclein preformed fibril (PFF)-induced pathological aggregates, and rescued synaptic
protein loss and neuronal death. Moreover, intraperitoneal administration of these exosomes into the mice with intra-striatally injected α-
synuclein PFF reduced the pathological α-
synuclein aggregates and improved motor impairments. In conclusion, we demonstrated that the aptamers targeting α-
synuclein aggregates could be effectively delivered into the mouse brain by the RVG-exosomes and reduce the neuropathological and behavioral deficits in the mouse PD model. This study highlights the therapeutic potential of the RVG-exosome delivery of aptamer to alleviate the brain α-
synuclein pathology.