A Self-Assembled α-Synuclein Nanoscavenger for Parkinson’s Disease
Jingyi Liu, Chao Liu, Jinfeng Zhang, Yunming Zhang, Keyin Liu, Ju‐Xian Song, Sravan Gopalkrishnashetty Sreenivasmurthy, Ziying Wang, Yesi Shi, Chengchao Chu, Yang Zhang, Caisheng Wu, Xianhua Deng, Xingyang Liu, Jing Song, Rongqiang Zhuang, Shuqiong Huang, Pengfei Zhang, Min Li, Lei Wen, Yun‐wu Zhang, Gang Liu
Abstract
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 analogue-based nanoscavenger (NanoCA) is engineered to be capable of a 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 aggregates of α-syn in the midbrain of an MPTP mouse model of PD. Our findings provide a clinically translatable therapeutic strategy aimed at neuroprotection and disease modification in PD.