Designing biomaterial-based oral protein drug-delivery systems for therapeutics

• Systematic review of biomaterial-based oral protein delivery systems. • Differentiates material-oriented from function-oriented design strategies. • Emerging carriers like engineered probiotics and ingestible robots are evaluated. • Discusses clinical translation hurdles and future multidisciplinary outlooks. Protein therapeutics have garnered significant attention owing to their high efficacy and specificity for treating various diseases. Compared with small-molecule drugs, protein therapeutic drugs exhibit stronger therapeutic effects, fewer side effects, and enhanced targeting capabilities. Owing to their advantages in patient acceptance and compliance, oral protein therapeutics may provide an alternative in selected indications. However, the harsh gastrointestinal environment, characterized by low pH and numerous proteases, is incompatible with the large size and poor membrane permeability inherent to protein-based drugs. Biomaterials, which have been considered the preferred solution to these challenges since the last century, have undergone vigorous development in recent years. This review summarizes novel biomaterial-based oral delivery systems such as nanoparticles, hydrogels, ionic liquids, and supramolecular systems. This review examines the advantages and limitations of material-driven strategies, which rely on inherent material properties, and function-driven strategies, for which clinical outcomes are predefined and delivery systems are precisely engineered. This review also outlines future research directions for oral protein drugs through expanded thinking and multidisciplinary collaboration. This study aims to accelerate clinical entry and transform suitable laboratory cases into replicable and widely applicable clinical strategies.