Oral vaccine delivery systems: Gastrointestinal barriers, gut microbiota, and emerging engineering strategies.

Oral vaccines present significant advantages, including ease of administration, high patient compliance, and the ability to elicit both mucosal and systemic immunity. However, their clinical translation faces challenges such as gastrointestinal barriers, immune tolerance, and individual variations in the gut microbiota. This review systematically summarizes the physiological and immunological barriers to oral vaccination and evaluates how the gut microbiota may influence intestinal vaccine-associated immunity. Particular attention is given to the advancement of oral vaccine delivery systems, including engineered nanocarriers, microbial vectors, and nonliving bacterial derivatives, with platform-specific consideration of antigen protection, mucus transport, epithelial uptake, intracellular delivery, and biosafety. Furthermore, the translational potential of these innovative approaches and future research directions are also discussed. This review aims to provide a comprehensive and forward-looking perspective for developing effective oral vaccination strategies.