Neuron Mitochondria Targeted “Zipper Peptide” Delivery for VHL‐Inhibiting Therapy in Parkinson's Disease

ABSTRACT Von Hippel‐Lindau (VHL) emerges as a promising target for neuroprotective treatment in Parkinson's disease (PD), but the challenging druggability hampers therapeutic development. Herein, we report a leucine zipper‐inspired peptide design for VHL‐targeting therapy, in which spontaneous formation of α‐helical structure yields high affinity and biostability, and a symmetrical hetero‐charge distribution on the α‐helix is easier to zip peptide into nanogel, followed by complexing with lipids and T7 peptide for dopaminergic neuron‐targeted mitochondria therapy. After systemic administration, the peptide‐lipid nanocomplex could reach dopaminergic neurons within 2 h, and release the VHL‐inhibiting peptide upon acidic pH to effectively disrupt VHL/Dishevelled‐2 (DVL‐2) interaction. Downstream β‐catenin and hexokinase 2 (HK2) proteins are elevated, promoting mitochondrial homeostasis, metabolic activity, and energy production for neuronal protection. The VHL‐targeting peptide therapy effectively ameliorates neurodegenerative pathologies and motor/coordination deficits in both MPTP‐induced injury and α‐synuclein overexpression PD models. Collectively, this study provides an innovative peptide drug design and a dopaminergic neuron‐targeting strategy for the neuroprotective treatment of PD.