Peptides represent a promising therapeutic class with the potential to alleviate many severe diseases. A key limitation of these active molecules relies on the difficulties for their efficient oral administration. The objective of this work has been the rational design of polymer nanocapsules (NCs) intended for the oral delivery of peptide drugs. For this purpose, we selected insulin glulisine as a model peptide. The polymer shell of the NCs was made of a single layer of protamine, a cationic polypeptide selected for its cell penetration properties, or a double protamine/polysialic acid (PSA) layer. Insulin glulisine-loaded protamine and protamine/PSA NCs, prepared by the solvent displacement method, exhibited a size that varied in the range of 200-400 nm and a neutral surface charge (from +8 mV to -6 mV), depending on the formulation. The stability of the encapsulated peptide was assessed using circular dichroism and an in vitro cell activity study. Colloidal stability studies were also performed in simulated intestinal media containing enzymes and the results indicated that protamine NCs were stable and able to protect insulin from the harsh intestinal environment, and that this capacity could be further enhanced with a double PSA-Protamine layer. These NCs were freeze-dried and stored at room temperature without alteration of the physicochemical properties. When the insulin-loaded protamine NCs were administered intra-intestinally to diabetic rats (12 h fasting) it resulted in a prolonged glucose reduction (60%) as compared to the control insulin solution. This work raises prospects that protamine NCs may have a potential as oral peptide delivery nanocarriers.