Abstract

Reactive oxygen species (ROS) - induced oxidative stress damage of dopaminergic neurons is the principal etiology of Parkinson's disease (PD). While most nanoenzymes can catalyze the breakdown of ROS present in the brain, they cannot eradicate the source of ROS production attributed to damaged mitochondria. Herein, we introduce a Co-doped Prussian blue (PB/Co) nanozyme that demonstrates multi-enzyme-like coordinated activity for scavenging present ROS and triggers mitophagy to remove damaged mitochondria. To further augment the brain entry efficiency of PB/Co nanozyme, we encapsulated it in 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 2,3-bis (palmitoyloxy)propyl-2-(trimethylammonio)ethylphosphate (DPPC) cationic liposomes and developed a non-invasive inhalable nanospray ((PB/Co)@DD) that permeates the brain via the olfactory bulb. In the PD mice model, (PB/Co)@DD nanospray induced mitophagy in the striatum to eliminate the ROS production source, preventing excessive ROS-induced sustained damage to dopaminergic neurons and averting the buildup of α-synuclein deposits, thereby ultimately restoring motor function in PD mice. Our research lays the foundation for catalytic therapy to eliminate abnormal mitochondria via the induction of mitophagy in PD mice models and highlights the potential of inhalable nanoenzymes as a non-invasive therapeutic strategy for the treatment of neuroinflammatory diseases.