A histidine-functionalized ROS scavenging hybrid nanozyme for therapeutic application in Parkinson's disease pathogenesis

Abstract

Oxidative stress-mediated neurotoxicity is one of the significant molecular consequences in the progression of neurodegenerative diseases like Parkinson's disease (PD). Although many genetic mutations are implicated in developing familial and sporadic PDs, the progressive degeneration of dopaminergic neurons still lacks therapeutic intervention. Biocompatible nanomaterials with enzyme-like characteristics, especially SOD1 activity to scavenge excessive reactive oxygen species, can serve as an effective tool to treat PD pathogenesis. Here we report novel histidine-functionalized zinc oxide nanoparticles (ZnNPs-H) and the corresponding copper-doped nanoparticles (ZnCuNPs-H) mimicking SOD1 activity. The functionalized NPs exhibit superior nanozyme activity by robust reactive oxygen species (ROS) scavenging potential compared to previously reported NPs in vitro. The functionalized NPs exhibited excellent biocompatibility in the neuronal cellular model and were targeted efficiently into mitochondrial compartments. The NPs showed robust superoxide dismutase nanozyme activity and scavenged the excess ROS upon rotenone and lung cancer screen-1 (LCS-1) treatment. The nanozyme effectively substituted the endogenous functions of SOD1 and reinstated the cellular redox homeostasis. Most importantly, the NPs rescued neuronal cells from the toxic effects of MPP⁺ conditions and restored the mitochondrial health associated with cellular morphology, highlighting their neuroprotective role in preventing Parkinson's disease pathogenesis, thus opening a therapeutic strategy for disease management.