It is aimed to develop a safe and effective oral gene delivery platform technology, taking advantage of the physiological enterohepatic circulation to treat insulin-independent diabetes patients by systemically producing an incretin, glucagon-like peptide 1 (GLP-1). The epithelial cells (enterocyte) in the gastrointestinal tract (GIT) has a high turnover rate (~3.5 days) in humans, and the ileum is largely responsible for recycling free and conjugated bile acids (collectively, BA) to the liver at a rate of 15-30 g/day with ~95% efficiency. We found that nanoparticles can be actively absorbed through bile acid recycling pathways, though by altered mechanisms. It is proposed in this grant application to leverage ileum enterocytes (ileocytes) as disposable protein factories, which can be transfected by non-viral gene vectors in a selective manner via bile acid transporter-mediated mechanisms, to supply systemic GLP-1. Selective transfection of the ileocyte would reduce exposure of the internal organs to toxicity from cationic non-viral vectors and to potential permanent insertion mutations in long- lasting cells in the body, while the continuous systemic supply of GLP-1 will be achieved by transfecting the cells at a regular interval by oral administration. We intend in this study 1) to better understand the transport pathways of anionic nanoparticles conjugated with BA, 2) to formulate an oral gene delivery system with a unique anionic polymer that is safe and carries its own supply of the energy molecule, i.e., adenosine triphosphate (ATP) to power transcription and translation, 3) to selectively target ileocytes by oral administration of non-viral gene carriers and minimize the transport of the carriers into systemic circulation and other internal organs, and 4) to treat type 2 diabetic animal models. The therapeutic output of twice-a-week GLP-1 gene oral administration will be compared with twice-a-day injections of Exendin-4 (a GLP-1 receptor agonist).