Parkinson’s disease (PD) is the second most common neurodegenerative disease, posing a significant threat to an individual’s health, particularly among the elderly. An incomplete understanding of the pathogenesis underlying PD renders the single therapeutic model ineffective. Oxidative stress and abnormal alpha-synuclein (α-Syn) aggregation are two crucial factors accounting for dopaminergic neuron loss. Therefore, combined PD therapy that inhibits and reduces α-Syn aggregation and regulates the balance of reactive oxygen species (ROS) holds promise. In this study a novel nanodrug, polydopamine-based curcumin-loaded nanoparticles (PC NPs), based on polydopamine (PDA)-assembled curcumin (Cur) nanoparticles was designed, which was then modified with a peptide obtained from rabies virus glycoprotein (RVG) 29 (obtained RPC NPs) to target the brain. Cur and PDA of ROS-responsive nanoparticles (RPC NPs) significantly scavenged a broad spectrum of ROS. Cur inhibited and removed α-Syn aggregation, thus protecting PC12 cells from rotenone-induced cell death. RPC NPs were also shown to prolong the lifespan of Caenorhabditis elegans and restored dopamine-dependent behaviors, including area-restricted searching, ethanol avoidance, and the basal slowing response, by using 6-hydroxydopamine (6-OHDA)-pretreated C. elegans wild-type Bristol (N2) and the nematode transgenic hus111 strain as models. In vivo animal studies showed that RPC NPs significantly lowered dopaminergic neuron damage and improved the neurobehavioral abnormalities in PD mice, while having no noticeable systemic side effects. RPC NPs also decreased α-Syn accumulation and reduced oxidative stress in the striatum and substantia nigra. This multifunctional synergetic strategy may provide a new candidate for highly efficient combination therapy in patients with PD.