Engineered inhalable nanocatalytic therapeutics for Parkinson's disease by inducing mitochondrial autophagy

Reactive oxygen species (ROS) -induced oxidative stress damage of dopaminergic neurons is the princi-pal 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 mito-chondria. 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-(trimethylam monio)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 nanos-pray 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 a-synuclein depos-its, 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 high-lights the potential of inhalable nanoenzymes as a non-invasive therapeutic strategy for the treatment of neuroinflammatory diseases.(c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study introduces a Co-doped Prussian blue (PB/Co) nanozyme that can scavenge existing ROS and induce mitophagy to eliminate damaged mitochondria. By encapsulating PB/Co nanozyme in two cationic liposomes and developing a non-invasive inhalable nanospray ((PB/Co)@DD), the brain entry efficiency of PB/Co nanozyme is further enhanced. The research shows that (PB/Co)@DD nanospray can induce mitophagy to eliminate ROS production source and restore motor function in PD mice models.