Abstract The global CNS pharmaceutical market is expected to grow significantly, overtaking the cardiovascular therapeutics market in the next 10 years. Although much work has been devoted to finding drugs that can cross the BBB into the brain, no single approach has worked for all drugs. The lack of technology to effectively cross the BBB or the blood-tumor barrier prevents researchers from providing effective therapeutics for most patients with brain disorders. Drug loaded nanoparticles (NPs) can hide the unfavorable drug's physicochemical characteristics, which hinders its ability to cross the BBB. In this study, we investigate the effect of different surfactant coatings, in a single or a blend form, on polymeric NPs loaded with model dyes and drugs on the brain drug uptake. Different NP formulations are conveyed using different cores ((Poly Lactic-co-Glycolic Acid (PLGA) and Chitosan) and coat materials (tweens, poloxamers, thiamine, polyethylene glycol (PEG), propylene glycol (PG) and spans). Chitosan core was formulated via ionic gelation technique. PLGA core was formulated via solvent evaporation technique. Different surfactants with different HLB (Hydrophilic Lipophilic Balance) values were applied as coating materials for the NPs. All NP formulations were characterized with respect to their size; charge, stability, in-vitro drug release to reach the optimal formulation. Female CD-1 mice were used to evaluate the drug brain uptake. Harvesting of the brain takes place within 60 seconds of animal sacrifice. Animals were euthanized, and brain tissue were removed and homogenized. Concentration of Rodamine B (Model dye) in the brain homogenates was analyzed via HPLC. The developed uncoated Chitosan NPs are in the size range of 50-100 nm with small polydispersity Index (PDI) (∼ 0.3) and a reproducible zeta potential of ∼ +19mV. After coating with tween-80 the zeta potential has decreased to -5 mV. The Tween-80 coated NPs were visualized via Transmission Electron Microscope (TEM). The particle size of the coated NP increased over the uncoated one from ∼ 100 nm to (150 - 200 nm). Finally, brain RodamineB concentration was significantly higher in case of tween-80 coated Chitosan and PLGA compared to uncoated NPs. The use of the novel drug carrier systems for drug targeting to brain is a promising alternative to conventional CNS therapy. The currently used polymers in this study are nontoxic, biodegradable, and biocompatible. The surfactant coated NPs for brain drug delivery is a promising technique to enhance brain uptake. The use of the surfactant coat could aid the solubilization of endothelial cell membrane lipids leading to membrane fluidization and enhanced drug permeability at the BBB. Citation Format: Mohamed I. Nounou, Salma Saudi, Ola Elnoweam, Dalia Alian, Amal El-Kamel. Surfactant coated nanoparticles for brain metastases: A brain uptake perspective. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B39.