Biomimicking neuromelanin reverses the gait deficits and dopaminergic neuronal loss in the Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor dysfunction, including gait deficits. Emerging evidence suggests that oxidative stress and ferroptosis play pivotal roles in dopaminergic neuronal loss in PD. In this study, polydopamine nanoparticles (PDA NPs) are introduced as synthetic neuromelanin to exert neuroprotective effect in 6-OHDA-induced PD models. Biomimicking neuromelanin exhibited robust neuroprotection by scavenging reactive oxygen species (ROS) and normalizing iron homeostasis, thereby mitigating iron overload, suppressing lipid peroxidation, and inhibiting ferroptosis. Mechanistically, PDA NPs effectively reversed dysregulation of iron metabolism by inhibiting 6-OHDA-induced up-regulation of iron uptake (DMT1) and down-regulation of efflux (FPN1) proteins, thereby reducing intracellular iron overload. Additionally, PDA NPs suppressed ferritin heavy chain (FTH) expression and restored antioxidant enzyme activity (GPX4 and SOD), alleviating lipid peroxidation and inhibiting ferroptosis. In vivo, PDA NPs significantly restored motor and gait parameters in PD mice, as evidenced by improvements in behavioral tests and dynamic gait analysis. PDA NPs also preserved tyrosine hydroxylase (TH) levels in the substantia nigra and reduced microglial activation, indicating both dopaminergic neuron protection and anti-inflammatory effects. These findings provide new insights into the multi-targeted neuroprotective mechanisms of biomimicking neuromelanin and suggest a promising and innovative therapeutic strategy for the treatment of PD.