α-Synuclein targeted therapy with multiple pathological improvement for Parkinson's disease by macrocyclic amphiphile nanomedicine.

The toxic species formed by the pathological aggregation of α-synuclein (α-Syn) is one of the core pathogenic mechanisms in Parkinson's disease, leading to mitochondrial dysfunction, oxidative stress and ultimately degeneration and loss of dopaminergic neurons. Developing effective inhibitors targeting α-Syn fibrillization critically requires the simultaneous achievement of (1) strong and selective binding of α-Syn for efficient disintegration of fibrils, as well as (2) robust transmembrane capability for efficient cellular uptake. Herein, the co-assembly of guanidinium-modified calixarene (GCA) and cyclodextrin (CD), termed GCA-CD, is screened fully accommodating these conditions. GCA-CD binds tightly and selectively towards α-Syn, thereby effectively inhibiting α-Syn aggregation and disintegrating its fibrils, meanwhile the guanidinium of GCA can additionally improve the transmembrane capability of the co-assembly. In vivo investigations demonstrate that the GCA-CD nanomedicine significantly rescues motor deficits and nigrostriatal degeneration of PD-like rats by decreasing the content of α-Syn as well as restoring mitochondrial dysfunction and suppressing oxidative stress. Astonishingly, transcriptome analysis further reveals the role of GCA-CD in dampening cuproptosis through inhibiting FDX1/LIAS signaling pathway, highlighting the multifaceted therapeutic effects of the co-assembly in PD. The findings in this study underscore the comprehensive exposition on the actual function mechanisms of the therapeutic agents, thereby providing valuable insights for informing material design.