Systemic therapy upon oral delivery of biologics, such as peptide and protein drugs is limited due to their large molecular size, their low
enzymatic stability and their inability to cross the intestinal epithelium. Ways to overcome the epithelial barrier include the use of peptide-based
excipients such as the cell penetrating peptides (CPPs) and the tight junction modulating peptides (TJMPs), which are able to translocate across
the cellular membranes in a non-disruptive way or reversibly modulate the integrity of intercellular tight junctions (TJs), respectively. However,
because of the harsh environment throughout the gastrointestinal (GI) tract, chemical stability is an inherent challenge when employing amino
acid-based excipients for oral delivery, and multiple approaches have been investigated to improve this. The exact mechanisms of transepithelial
translocation are discussed, and it is believed that CPP-mediated translocation involves transcytosis and/or direct translocation through the
epithelial cells; whereas TJMP-mediated translocation is dependent on interaction with transmembrane or peripheral TJ proteins. This review
focuses on the CPPs and the TJMPs currently employed as excipients for oral delivery of peptide and protein drugs highlighting recent studies
and the most promising compounds from these classes of peptide excipients.