Cell-penetrating peptide (CPP) was linked to insulin to form insulin-CPP hybrids. The intestinal absorption efficiency of CPP hybridized insulin was 6-8 times increased compared to normal insulin as tested on Caco-2 cell monolayer, a widely used in vitro model for intestinal absorption. Insulin-CPP hybrid transportation seemed to be through an active and transcytosis-like mechanism. Importantly, insulin in hybrids kept intact after they passed through the Caco-2 cell monolayer. This study provides a new clue for oral insulin development. (C) 2005 Elsevier Inc. All rights reserved.