Essential requirements for such nanocarriers are high stability and specificity, suitable tissue distribution, satisfactory cell penetration and efficient cytoplasmic or nuclear delivery. Due to the advantage of their size, nanoscale systems have been shown to be efficient drug delivery systems and may be useful for encapsulating drugs, enabling more precise targeting with a controlled release. Their use may address some of the most pressing challenges in drug delivery, such as solubilizing poorly water-soluble drugs, protecting labile drugs from degradation, and delivering drugs selectively to disease sites. These nanosized structures penetrate tissue, facilitate efficient uptake of the drug by cells, enable successful drug delivery, and ensure activity at the targeted location. The uptake of nanostructures by cells is much higher than that of large particles. Modifying or functionalizing nanoparticles to deliver drugs through the blood-brain barrier for targeting maladies of the central nervous system has been one superb outcome of medical nanotechnology. Since a wide variety of nanoparticles made of biological and/or synthetic materials are available, selecting suitable particles relies mainly on the type of therapeutic molecule to be delivered. Nanoparticular carrier systems designed for brain delivery of therapeutic drugs are composed of different materials, including mainly polymers, lipids, metals, or a combination of these materials (Figure ). In addition, nanoparticle (NP) formulations must provide high biocompatibility, biodegradability, low toxicity, and protein-mediated opsonization. Moreover, clearance by the reticuloendothelial system is an obstacle for NPs to overcome. Lipid-based NPs are widely used as carriers in drug and gene delivery. Various nanostructures have been utilized including solid lipid NPs, liposomes, and micelles (Figure ). For instance, stable nucleic acid lipid particles, incorporating a short peptide derived from rabies virus glycoprotein and encapsulating small interfering siRNAs, has been engineered to target mutant ataxin-3 in mouse models of SCA3 and reported successful in ameliorating motor behavior and neuropathological alterations. Solid lipid NPs composed of hydrogenated soya phosphatidylcholine 3-nitropropionic acid were used to deliver intranasally the neuroprotector rosmarinic acid to the brain of rats for effective management in Huntington's disease. Furthermore, hybrid polymer/lipid NP systems comprising poly (lactic-co-glycolic acid) and solid lipid (Witepsol E85) were functionalized with a peptide-binding transferrin receptor to enhance their capacity to cross the blood-brain barrier to target human brain endothelial cells and deliver siRNAs. Polymeric NP are another successful pharmaceutical nanocarrier. Hydrophobic polymers such as poly (L-lysine), polyethyleneimine, poly (lactic acid), poly (lactic-co-glycolic acid), and poly (ε-caprolactone), as well as hydrophilic polymers including chitosan, alginate, gelatin, and hyaluronic acid, have been commonly used. These polymers, alone or in combination, can entrap biomolecules of interest for molecular therapies. For example, brain distribution of aripiprazole, a small molecule drug reducing the levels of mutant ataxin-3 protein 163, 166 , was expedited when encapsulated into poly(ε-caprolactone) NPs and administered intranasally to rats. Poly(ε-caprolactone)/ Pluronic F-68 NPs have been reported effective in mediating the delivery of the antioxidant curcumin to neural-like cells. NPs based on natural polymers such as chitosan and cyclodextrins have been found effective delivery systems because of their ability to cross the blood-brain barrier. Self-assembling modified β-cyclodextrin nanoparticles were applied as neuronal siRNA delivery vectors and reported successful in alleviating motor deficits in mouse model of Huntington's disease. 171 Metallic NPs are also efficient pharmaceutical nanocarriers because of their unique physiochemical properties. Aggregation of polyQ-containing mutant huntingtin has been hindered in neuronal cells in Huntington's disease mouse brains by using an Fe2O3 polyacrylate-coated and covalently conjugated poly(trehalose) nanocarrier system. A similar metallic NP-based approach may be scaled to treat polyQ SCAs.