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Diabetes Mellitus (DM) is a common endocrine disorder responsible for high morbidity and mortality worldwide. The standard medical treatment for DM is oral hypoglycemic agents and/or insulin. Exenatide, a glucagon-like peptide, has been used to reduce blood sugar and treat DM in the last 20 years. Exenatide administration is limited to parenteral routes. The development of an orally administered Exenatide represents a worthy study that provides significant benefits to patients with diabetes by improving compliance and adherence to the treatment and reduce the burden of frequent injections and enhance treatment outcomes. The aim of the study is to prepare Exenatide as an oral drug delivery system by combining the advantages of nanoencapsulation with the use of an oily vehicle using fatty acids. Method: The polyelectrolyte complexation method was used to prepare Exenatide-chitosan complexes (PEC) as an aqueous environment in order to create orally administered Exenatide. The potential of PEC -fatty acids nanoparticles as oral delivery carriers of Exenatide was studied. Results: The sizes of the formed nanodispersed particles were different when loaded with diluted chitosan or PEC. The vortex mechanical mixing method produced superior results and provided about 20% greater Exenatide gastrointestinal protection than the stirring mechanical method. The results indicated that hydroxypropyl-β-cyclodextrin (HP-β-CD) had a more promising effect on oleic acid formula (F4), providing 87.1% Exenatide gastrointestinal protection but with a larger nanodispersed particle size of 200 nm. However, it did not produce significantly better results for linoleic acid (F8), which provided 81.6% gastrointestinal protection and a nanodispersed particle size of 210 nm. An in vivo study showed that formula F4 has the Cmax of Exenatide with Tmax of 3 h. Blood glucose was effectively reduced to a level of 91 mg/dl level within 3 h, with a sustained reduction up to 8 h. Conclusion: Exenatide could be protected from gastrointestinal enzymes by incorporation into chitosan lipid-based formulation. The vortexing mechanical mixing method is preferred method for the preparation. The use of the HP-β-CD improved gastrointestinal protection. The formula F4 is a promising oral alternative to the paraenteral Exenatide