Brain gene-targeting technology is used to reversibly normalize tyrosine hydroxylase (TH) activity in the striatum of adult rats, using the experimental 6-hydroxydopamine model of Parkinson's disease. The TH expression plasmid is encapsulated inside an 85-nm PEGylated immunoliposome (PIL) that is targeted with either the OX26 murine monoclonal antibody (MAb) to the rat transferrin receptor (TfR) or with the mouse IgG2a isotype control antibody. TfRMAb-PIL, or mIgG2a-PIL, is injected intravenously at a dose of 10 μg of plasmid DNA per rat. TfRMAb-PIL, but not mIgG2a-PIL, enters the brain via the transvascular route. The targeting TfRMAb enables the nanocontainer carrying the gene to undergo both receptor-mediated transcytosis across the blood-brain barrier (BBB) and receptor-mediated endocytosis into neurons behind the BBB by accessing the TfR. With this approach, the striatal TH activity ipsilateral to the intracerebral injection of the neurotoxin was normalized and increased from 738 ± 179 to 5486 ± 899 pmol/hr per milligram of protein. The TH enzyme activity measurements were corroborated by TH immunocytochemistry, which showed that the entire striatum was immunoreactive for TH after intravenous gene therapy. The normalization of striatal biochemistry was associated with a reversal of apomorphine-induced rotation behavior. Lesioned animals treated with the apomorphine exhibited 20 ± 5 and 6 ± 2 rotations/min, respectively, after intravenous administration of the TH plasmid encapsulated in mIgG2a-PIL and TfRMAb-PIL. These studies demonstrate that it is possible to normalize brain enzyme activity by intravenous administration and nonviral gene transfer.