Multi-Enzyme Co-Expressed Ruthenium dioxide nanoparticles activate mitochondrial autophagy and regulate oxidative stress for Alzheimer's disease treatment

Mitochondrial damage induced by reactive oxygen species and mitochondrial autophagy dysfunction are closely related to the pathogenesis of Alzheimer's disease (AD). Therefore, the recovery of mitochondrial autophagy disorder is crucial in maintaining mitochondrial homeostasis, protecting neurons, and improving AD. Herein, Ruthenium dioxide nanoparticles (RuO 2 ) have multi-enzyme activities, such as superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD). And the multi-enzyme activity depends on the size, oxygen vacancy, morphology and specific surface area of the nanoparticles. The ultrasmall Ruthenium dioxide showed excellent antioxidant activity in the enzyme activity experiment. The results of in vitro experiments show that RuO 2 can restore damaged neurons by clearing Aβ and H 2 O 2 -induced reactive oxygen species (ROS). It maintains mitochondrial function, restores mitochondrial autophagy and normalizes mitochondrial dysfunction, thereby restoring injured neuronal cells. At the same time, it also showed the ability to regulate microglia polarization, inhibit microglia overactivation, and relieve neuroinflammation. After screening the results of enzyme activity experiment and in vitro experiment, sRuO 2 with small particle size and good enzyme activity was selected for in vivo experiment. sRuO 2 can inhibit oxidative stress in vivo , reduce the burden of Aβ, regulate the neuroprotective function of microglia and improve neuroinflammation. It ultimately improve memory decline and cognitive impairment in Aβ mice. These results suggest that sRuO 2 nanoenzymes with antioxidant activity have great potential in the treatment of AD. The multi-target strategy also offers a promising treatment option for AD.