Glial cell line-derived neurotrophic factor (GDNF) has been shown to be neuroprotective toward substantia nigra (SN) dopamine neurons in animal models of ParkinsonÍs disease (PD) and in some clinical trials. æHowever, its delivery to brain has required invasive surgical routes that are untenable for many patients with PD. æThe goal of these experiments was to test whether intranasal delivery of a GDNF expression plasmid could protect dopamine cells in the rat 6-hydroxydopamine (6-OHDA) model of PD. æIf successful, intranasal delivery of pGDNF could provide a renewable source of GDNF within the brain without need for surgical injections or frequent re-dosing. æææRats were given intranasal saline, naked pGDNF or pGDNF in a PEGylated polylysine nanoparticle (NP) preparation 7 days prior to receiving a unilateral 6-OHDA lesion. æThree weeks after 6-OHDA injection, rotational behavior to 5 mg/kg d-amphetamine was assessed, followed by sacrifice. æTyrosine hydroxylase (TH) immunohistochemistry, an index of dopamine neurons, revealed a significant reduction in lesion severity in the SN and striatum of rats given intranasal pGDNF NPs versus those given naked pGDNF or saline. ææThis was revealed as significantly higher SN dopamine cell counts and greater TH staining densities in rats given pGDNF NPs. æIn addition, rotational behavior was reduced in rats treated with pGDNF NPs. æThese results demonstrate the utility of intranasal delivery of pGDNF NPs as a non-invasive means of gene therapy for PD and possibly other diseases of the brain.