Re-engineering insulin for oral delivery: structural modifications, advanced formulation strategies, and future directions

Oral insulin delivery represents a transformative approach to diabetes management, offering improved patient compliance and physiological insulin delivery patterns compared to subcutaneous injection. However, multiple gastrointestinal barriers, including enzymatic degradation, mucus entrapment, epithelial impermeability, and first-pass metabolism, have limited oral bioavailability to below 1% for unmodified insulin. This review comprehensively examines contemporary strategies to overcome these barriers. We analyze structural modifications of insulin, including PEGylation, lipidation, cyclization, and glycoengineering, which enhance stability while maintaining biological activity. The analysis extends to sophisticated formulation technologies incorporating nanocarriers (polymer-based, lipid-based, inorganic nanocarriers, and metal organic frameworks), biomimetic systems, and stimuli-responsive mechanisms for protection and delivery. A central focus is on absorption-enhancing strategies, which range from chemical permeation enhancers to precise biological mechanisms like receptor-mediated transcytosis and other active transport pathways. Emerging tools such as microbiome-based carriers and smart devices are also discussed. Despite significant progress in preclinical models, challenges remain in manufacturing scalability, inter-patient variability, long-term safety, and regulatory approval. Future directions emphasize hybrid delivery systems, digital health integration, and personalized formulations. Realizing clinically viable oral insulin requires continued multidisciplinary collaboration addressing biological, technological, and translational barriers to transform diabetes care.