ABSTRACT Oral delivery of peptide therapeutics remains a major challenge due to extensive enzymatic degradation, mucus entrapment, limited epithelial permeability, active efflux, and hepatic first‐pass metabolism, all of which restrict systemic exposure. Recent advances in nanocarrier engineering and AI‐driven design are beginning to overcome these barriers through synergistic innovations in medicinal chemistry, formulation science, and clinically validated enhancer platforms. Mechanistic insights into gastrointestinal physiology have enabled the rational development of technologies such as SNAC and TPE, supporting gastric or intestinal transcellular uptake and establishing the first clinically approved oral peptide formulations. Parallel progress in peptide engineering including cyclization, D‐amino acid substitution, lipidation, and transporter‐targeted conjugation enhances proteolytic stability and epithelial interaction, while next‐generation polymer–lipid hybrids, mucus‐penetrating carriers, bile‐acid–guided systems, and stimuli‐responsive biomaterials provide tunable protection and controlled release across the GI tract. Device‐assisted platforms such as LUMI, SOMA, and RaniPill further expand this toolkit by bypassing epithelial barriers altogether. These technological gains intersect with sustainable manufacturing and green bioprocessing considerations essential for scalable clinical translation, along with persistent global health challenges in LMIC settings. Collectively, these developments highlight a decisive shift toward clinically viable, patient‐centric oral peptide therapeutics and outline a forward SDG‐aligned trajectory in which computational design, eco‐efficient production, and advanced biomaterial systems converge to enable reliable systemic and local delivery via the oral route.
JEYAVELKUMARAN et al. (Fri,) studied this question.