Mitochondrial Enzymes Mimetic Ultrasmall Palladium Nanozymes Prevent Senescence and Neurodegeneration Through Metabolic Reprogramming

Abstract Nanomaterials have been widely used to scavenge reactive oxygen species (ROS) and relieve mitochondria oxidative damage. However, developing nanomedicines that not only remove ROS but also accelerate the repair of dysfunctional mitochondria remains challenging. This study identifies polyvinylpyrrolidone (PVP)‐modified palladium nanoparticles (PdP NPs) as mimics of cytochrome c oxidase (C c O) and superoxide dismutase (SOD), showcasing their potential as multifunctional nanoreactors to activate mitochondria for aging alleviation and neuroprotection. PdP NPs treatment enhances mitochondrial respiratory chain function, scavenges excessive ROS, thus alleviates cellular energy scarcity of aging individuals. Additionally, PdP NPs improve mitochondrial dynamics, promote biogenesis, and induce mitochondrial unfolded protein response (UPR mt ), strengthening mitochondrial integrity and homeostasis for better therapeutic outcomes. In vivo evaluations reveal significant anti‐aging effects, with the nanozymes notably reducing neurodegeneration and improving neuronal survival. This work highlights PdP NPs as a multifunctional nanotherapeutic platform capable of rewiring mitochondrial metabolism and homeostasis, offering a promising strategy for aging‐related disease management.