Engineering pH-responsive probiotic carriers for oral delivery: Design principles, gastrointestinal fate, and translational perspectives.

Abstract

Probiotics play important roles in maintaining gut homeostasis and promoting host health. However, their oral delivery remains challenging because of substantial viability loss during gastrointestinal transit. pH-responsive delivery systems have emerged as a promising strategy to improve probiotic survival and achieve site-specific intestinal release by exploiting the natural pH gradient along the gastrointestinal tract. This review examines the physiological basis of pH-responsive probiotic delivery, including gastrointestinal pH variation and the major biological barriers affecting probiotic fate. Key design principles are discussed, with emphasis on protonation-deprotonation behavior, protection-release coupling, and multilayer structural engineering. Recent advances in material platforms, including polysaccharide matrices, protein-polysaccharide composites, enteric-coated systems, hybrid materials, and emulsion-based carriers, are summarized together with fabrication approaches such as extrusion gelation, emulsion templating, coating technologies, and microfluidics. The functional evolution of these systems is highlighted, demonstrating a shift from simple gastric protection toward gut-targeted delivery, prolonged intestinal retention, disease-oriented applications, and multifunctional probiotic systems. Current evaluation methods are critically assessed, particularly regarding the limitations of simplified in vitro digestion models and inconsistent viability metrics. Finally, the translational potential of pH-responsive probiotic carriers is discussed from the perspectives of material safety, processing compatibility, sensory impact, and scalability. Future developments are expected to focus on food-grade, adaptive, and function-oriented delivery systems that more effectively integrate gastrointestinal physiology with application-specific delivery objectives.