Chiral Carbon Nanodots Modulate α‐Synuclein Homeostasis to Combat Parkinson's Disease

Inhibiting α-synuclein (α-syn) aggregation is an effective treatment for Parkinson's disease (PD), and chiral recognition of proteins offers a novel strategy for designing efficient inhibitors. However, the impact of chiral selectivity on α-syn aggregation and its regulatory mechanisms remain ambiguous. In this work, it is synthesized chiral carbon nanodots (CNDs), including L-CNDs, D-CNDs, and DL-CNDs, and found that D-CNDs exhibited the most potent inhibitory effect on α-syn aggregation. ¹H-¹⁵N heteronuclear single quantum coherence nuclear magnetic resonance spectroscopy revealed that CNDs primarily interact with α-syn through electrostatic interactions, with D-CNDs specifically targeting key aggregation-prone residues, thereby disrupting β-sheet formation and reducing fibril assembly. In contrast, L-CNDs and DL-CNDs exhibited limited inhibitory effects, attributed to their weak affinity for the non-amyloid-β component region. Moreover, CNDs efficiently crossed the blood-brain barrier, and D-CNDs significantly reduced α-syn accumulation, alleviated neuronal damage, and ameliorated cognitive function. This work underlines the critical role of chirality in modulating α-syn aggregation and provides a novel strategy for developing enantiomer-selective inhibitors for PD therapy.