Polydopamine nanoparticles restore cognition via targeted dopamine delivery and septo-hippocampal cholinergic activation.

Altered dopamine (DA) neurotransmission in key brain circuits underlies cognitive deficits across psychiatric and neurological disorders by disrupting working memory, attention, and executive function. Here, we introduce a novel, carrier-free nanotherapeutic approach using polydopamine nanoparticles (PDA NPs)-synthesized via oxidative self-polymerization of DA hydrochloride-for targeted DA supplementation and cognitive rescue. Uniform, spherical PDA NPs (~250 nm) exhibit excellent biocompatibility and cross the blood-brain barrier via endocytosis. In acidic environments, they degrade to release DA, which is internalized by endothelial and neuronal cells and subsequently converted into downstream catecholamines. In a mouse model of lipopolysaccharide-induced cognitive impairment, PDA NP treatment fully restored performance in Y-maze and novel-object recognition tests. Biochemical analyses showed that short-term administration elevated hippocampal DA, norepinephrine, and tyrosine, while prolonged treatment markedly increased acetylcholine levels. This long-term cholinergic enhancement was mediated by activation of septo-hippocampal projections via DA D2 receptor signaling in the medial septal nucleus. Together, these results establish PDA NPs as an effective, carrier-free platform for targeted DA delivery that not only replenishes catecholamines but also engages cholinergic circuits to ameliorate cognitive impairments.