Engineering oral hydrogels for versatile drug delivery: core technologies, disease applications, and industrial translation.

Oral drug delivery is preferred for patient compliance, but it's challenging for biologics and sensitive therapeutics due to the harsh gastrointestinal environment. Engineered oral hydrogels, enhanced through chemical modifications, offer superior entrapment efficiency and controlled release compared to traditional forms like capsules. Through innovative mechanisms, including stimuli-responsiveness, active adhesion, and microenvironmental modulation, oral hydrogels overcome key limitations associated with traditional oral formulations. These systems can achieve prolonged retention and site-specific controlled release in targeted areas of the gut, such as the colon, through chemical engineering strategies. Meanwhile, they can also be used as bioactive ingredients to regulate intestinal microbiota, restore the integrity of the mucosal barrier, and play a systemic therapeutic role in distal organs through the gut-brain axis and gut-immune axis. This review summarizes the research progress of oral hydrogel materials, focusing on their stimuli-responsive and mucus-adhesive designs for efficient drug delivery, as well as extended functions such as regulation of intestinal microbiota. It also addresses the challenges of clinical translation and examines bottlenecks and regulatory pathways to scale up through disease-specific cases. Finally, an integrated framework combining rational design, artificial intelligence, and translational science is proposed to bridge the gap from laboratory research to clinical applications.