Oral delivery of insulin holds great promise for improving patient compliance. However, the harsh gastrointestinal environment, the low permeability of the intestinal epithelium, and hepatic clearance of foreign particles remain key challenges in this area. Here, we report the site-specific adaptive milk-derived nanovesicles (MiNVs) capable of overcoming intestinal and hepatic barriers for oral insulin delivery. These MiNVs could bind natural IgG on their surface, enabling FcRn-mediated transcytosis by evading the lysosomal degradation pathway. Upon reaching the liver, MiNVs responded to the elevated levels of biothiols in the hepatic microenvironment, triggering site-specific insulin release. In type 1 diabetic rats, the oral bioavailability reached 20.4%, which is about 20-fold higher than that of free insulin. Notably, MiNVs showed effective glycemic control over long-term treatment in type 1 diabetic rat and minipig models. By integrating transepithelial transport and liver-specific responsiveness, the site-specific adaptability of MiNVs supports their promise in oral insulin administration.