Insulin expressed in the liver is essential for regulating glucose homeostasis.33 Physiologically, the insulin that is endogenously secreted by the pancreatic islets of Langerhans is transported to the liver by portal circulation.28 The in vivo studies demonstrated that the orally administered insulin plasmid NPs resulted in sustained therapeutic gene expression in mice with STZ‐induced diabetes, and the level of insulin expression was sufficient to ameliorate hyperglycemia in the diabetic mice over 10 d (Figure 6A). This evidence concerns the gene INS and diabetes mellitus.