Agnese Gagliardi,1 Donatella Paolino,1 Michelangelo Iannone,2 Ernesto Palma,3 Massimo Fresta,3 Donato Cosco3 1Department of Experimental and Clinical Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy; 2CNR, Section of Pharmacology, Institute of Neurological Sciences, Borgia, Italy; 3Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy Background: The use of biopolymers is increasing in drug delivery, thanks to the peculiar properties of these compounds such as their biodegradability, availability, and the possibility of modulating their physico-chemical characteristics. In particular, protein-based systems such as albumin are able to interact with many active compounds, modulating their biopharmaceutical properties. Zein is a protein of 20–40 kDa made up of many hydrophobic amino acids, generally regarded as safe (GRAS) and used as a coating material. Methods: In this investigation, zein was combined with various surfactants in order to obtain stable nanosystems by means of the nanoprecipitation technique. Specific parameters, eg, temperature, pH value, Turbiscan Stability Index, serum stability, in vitro cytotoxicity and entrapment efficiency of various model compounds were investigated, in order to identify the nanoformulation most useful for a systemic drug delivery application. Results: The use of non-ionic and ionic surfactants such as Tween 80, poloxamer 188, and sodium deoxycholate allowed us to obtain nanoparticles characterized by a mean diameter of 100–200 nm when a protein concentration of 2 mg/mL was used. The surface charge was modulated by means of the protein concentration and the nature of the stabilizer. The most suitable nanoparticle formulation to be proposed as a colloidal drug delivery system was obtained using sodium deoxycholate (1.25% w/v) because it was characterized by a narrow size distribution, a good storage stability after freeze-drying and significant feature of retaining lipophilic and hydrophilic compounds. Conclusion: The sodium deoxycholate-coated zein nanoparticles are stable biocompatible colloidal carriers to be used as useful drug delivery systems. Keywords: nanoparticles, sodium deoxycholate, stabilizers, zein