The major challenge for obtaining high drug bioavailability of peptide biopharmaceuticals is to circumvent the intestinal barrier constituted road-block where the physiochemical properties of peptides, being relatively large macromolecules with medium to high hydrophilicity, constitutes an intrinsic challenge. Modifications that can be used to change the physiochemical properties of the peptides will often render them non-active except at a few selected positions that do not interfere with their binding to target receptors. Effective delivery of peptide biopharmaceuticals requires more advanced peptide engineering strategies and/or new drug delivery technology developments, which may need to be mutually optimized, hand-in-hand, to achieve radical improvement in oral delivery efficiency. We will innovate the next generation drug delivery systems that effectively transport peptide biopharmaceuticals across the small intestine, which can successively seek out target cells and tissues, and ultimately release the carried drugs with spatial and temporal control in a radically more efficient way than current state-of-the-art. The key challenge to be addressed is to mechanistically understand how a delivery system can be designed to transport biopharmaceuticals across the intestinal barrier with a design that provides high bioavailability of the drug to the target cells and tissues within animals and humans.