Navigating the complexity of oral peptide delivery: challenges and strategies to enhance oral bioavailability

Peptide therapeutics have emerged as a rapidly expanding drug class capable of modulating highly specific and previously inaccessible molecular targets. Maximizing the clinical and commercial potential of therapeutics, particularly in chronic indications, requires patient-friendly routes of administration with oral delivery often being preferred for its non-invasive nature. Peptides, however, often exhibit unfavorable physicochemical properties for epithelial permeability, paired with high polarity, charge, molecular size, and proteolytic instability. These factors collectively result in low and often insufficient systemic bioavailability. Recent advances in peptide chemistry have shifted the landscape of oral delivery. Structural modifications that enhance potency, metabolic stability, and half-life have enabled therapeutic efficacy even at low single-digit oral bioavailability, as demonstrated by clinically successful and late-stage candidates. Consequently, the central challenge is no longer feasibility, but optimization through designing formulation strategies that are mechanistically aligned with the physicochemical and pharmacokinetic properties of individual peptides. This review examines the key scientific barriers to oral peptide absorption and evaluates emerging strategies to address them, focusing on three interconnected domains: (1) functional excipients to overcome biological barriers; (2) translation of liquid prototypes into robust solid dosage formulations; and (3) integration of in vitro , in vivo , and computational tools to improve predictive accuracy and accelerate development. Collectively, these approaches outline a framework for data-driven optimization and potential route to de-risk translation of oral peptide therapeutics.