A Self-Assembled α-Synuclein Nanoscavenger for Parkinson's Disease

Although emerging evidence suggests that the pathogenesis of Parkinson's disease (PD) is closely related to the aggregation of alpha-synuclein (α-syn) in the midbrain, the clearance of α-syn remains an unmet clinical need. Here, we develop a simple and efficient strategy for fabricating the α-syn nanoscavenger for PD via a reprecipitation self-assembly procedure. The curcumin analog-based nanoscavenger (NanoCA) is engineered capable of controlled-release property to stimulate nuclear translocation of the major autophagy regulator, transcription factor EB (TFEB), triggering both autophagy and calcium-dependent exosome secretion for the clearance of α-syn. Pretreatment of NanoCA protects cell lines and primary neurons from MPP+-induced neurotoxicity. More importantly, a rapid arousal intranasal delivery system (RA-IDDS) was designed and applied for the brain-targeted delivery of NanoCA, which affords robust neuroprotection against behavioral deficits and promotes clearance of monomer, oligomer and aggregate...