Mitochondria-targeted ruthenium nanozyme as ROS scavenger and NAD+-booster to alleviate mitochondria dysfunction in Alzheimer’s disease

Modulating mitochondrial dysfunction by alleviating oxidative stress has recently emerged as a promising therapeutic strategy for Alzheimer’s disease (AD), but it ignores the fact of ROS regeneration caused by dysfunctional mitochondria. Herein, we developed a mitochondria-targeted ruthenium nanozyme, Ru@CP5-TPP, to enhance mitochondrial function by simultaneously scavenging reactive oxygen species (ROS) and eliminating damaged mitochondria. Ru@CP5-TPP was fabricated by modifying ultrasmall ruthenium nanoparticles (Ru NPs) with cationic pillar[5]arene (CP5), followed by the conjugation of the mitochondria-targeting molecule triphenylphosphine (TPP) through host-guest recognition. Under NIR-I laser irradiation, Ru@CP5-TPP can bypass the blood-brain barrier (BBB), target microglial mitochondria, and scavenge existing ROS through its intrinsic CAT-like and SOD-like activities. Moreover, by mimicking NADH oxidase (NOX), Ru@CP5-TPP catalyzes the conversion of NADH into NAD + , thereby inducing mitophagy and ultimately preventing ROS regeneration. As a result, Ru@CP5-TPP effectively alleviates mitochondrial dysfunction, inhibits Aβ deposition, relieves neuroinflammation, and ameliorates memory defects in an AD mouse model. This study provides a novel approach for the multi-target treatment of AD by leveraging the multi-enzyme activity of nanozymes. Download: Download high-res image (195KB) Download: Download full-size image Ru@CP5-TPP was constructed by modifying cationic pillar[5]arene (CP5)-capped Ru nanoparticles (Ru@CP5) with the mitochondria-targeting ligand TPP. Under NIR-I light irradiation, Ru@CP5-TPP can cross the blood-brain barrier (BBB), target microglial mitochondria, scavenge ROS, and promote mitophagy, thereby preventing ROS regeneration and ultimately alleviating Alzheimer's disease.