Parkinson's disease (PD) is characterized by the degeneration of the dopamine-producing cells in the substantia nigra. Early diagnosis and therapy is essential at the molecular level before initiation of symptomatic changes. Blood-brain barrier (BBB) penetration still remains a major challenge. Increased brain penetration and targeting can be achieved by formulating nanosized drug delivery systems using liposomes and niosomes. Other studies have been performed using pramipexole, but our study is novel in evaluating the penetration and antiparkinsonian effect of nanosized, polyethylene glycol (PEG) ylated pramipexole-encapsulated liposomes and niosomes. Nanosized, PEGylated, neutral and positively charged pramipexole-encapsulated liposomes and niosomes were formulated, characterized, and the release kinetics were evaluated. In vitro penetration of all formulations was evaluated using the BBB cell co-culture model. In vivo effectiveness of neutral, pramipexole-encapsulated liposomes and niosomes was evaluated in 6-hydroxydopamine (6-OHDA) lesioned rats by rotometer testing and autoradiography. All formulations exhibited approximately 10% encapsulation efficiency and around 100 nm particle sizes and fitted first-order release kinetics. All formulations were BBB permeable in vitro as determined by fluorescent images and fluorospectroscopy. Therefore, nanosized, neutral pramipexole-encapsulated niosomes showed better effects at a dosage approximately 9 times less than that administered using conventional pramipexole tablets for human in routine treatment. Nanosized PEGylated pramipexole liposomes and niosomes were blood brain barrier permeable. Nanosized pramipexole-encapsulated neutral niosomes showed potential therapeutic effects in a Parkinson's disease animal model depending on the nanosize and non-ionic surfactant properties of the niosomes. Further experiments are currently being performed to improve the therapeutic effects.