Strategies for overcoming multiple barriers of oral administration of protein and peptide therapeutics

Oral delivery of protein and peptide therapeutics (PPs) offers a non-invasive, patient-friendly alternative to parenteral administration, yet faces multiple formidable barriers due to the complex gastrointestinal (GI) environment. This review provides an overview of the latest advances of strategies developed to overcome the four main GI barriers: the harsh pH environment, enzymatic degradation, the mucus layer, and the intestinal epithelial barrier. We critically evaluate various approaches including chemical modifications, permeation enhancers, encapsulation techniques, and novel delivery systems like microneedles and nanoparticle-based carriers, each designed to protect PPs and enhance their bioavailability. A comparative analysis of the advantages and limitations of these strategies is presented, along with a discussion on how to integrate them synergistically for the effective overcoming of multiple GI tract barriers. Furthermore, we examine the current challenges associated with oral PPs drug delivery systems and explore future directions aimed at achieving successful therapeutic outcomes.