Mitochondrial-Targeting Ceria Nanoparticles as a Potential Antioxidant drug for Therapy of Alzheimer’s Disease.

Mitochondrial oxidative stress is an important pathologic factor in neurodegenerative diseases, including Alzheimer’s disease. Abnormal production of reactive oxygen species (ROS), resulting from mitochondrial dysfunction, leads to neuronal cell death. Ceria (CeO2) nanoparticles less than 5 nm are known to perform as powerful and recyclable ROS scavengers by exchanging between Ce3+ and Ce4+ oxidation states. Hence, targeting ceria nanoparticles specifically to mitochondria might be a promising therapeutic approach for neurodegenerative diseases. Here, we report the design and synthesis of triphenylphosphonium-conjugated ceria nanoparticles which localize to mitochondria of subicular cells due to their small hydrodynamic diameter (22 nm) and highly positive charge (+45 mV). The triphenylphosphonium-conjugated ceria nanoparticles diminish mitochondrial oxidative stress and suppress neuronal death in a 5XFAD transgenic Alzheimer’s disease mouse model after two months. The triphenylphosphonium-conjugated ceria nanoparticles alleviate reactive gliosis and morphological mitochondria damage observed in these mice. Altogether, our data indicate that the triphenylphosphonium-conjugated ceria nanoparticles are a potential therapeutic candidate for mitochondrial oxidative stress in Alzheimer’s disease.