On-Chip modeling of drug-gut interactions in Oral drug delivery.

The gastrointestinal tract is a dynamic ecosystem where biophysical forces, enzymatic gradients, and microbial metabolism converge to govern the fate of orally administered therapeutics. These multifactorial interactions-spanning shear stress, mucus transport, and microbial metabolism-collectively shape absorption, transformation, and therapeutic response. Such complexity drives the wide interindividual variability in oral pharmacokinetics and pharmacodynamics, challenging predictive modeling and formulation design. Capturing these intertwined processes requires experimental systems that bridge the physiological fidelity of human tissue with the analytical control of engineered models. Microphysiological Gut-on-a-Chip (GoC) platforms have emerged as promising tools that reconstruct human intestinal architecture and function with high precision. These devices integrate living epithelia, peristaltic motion, oxygen and nutrient gradients, immune and microbial co-cultures, and on-chip sensing within precisely engineered microenvironments. They enable direct observation and quantification of luminal-mesenchymal communication, barrier regulation, and metabolite exchange under physiologically relevant flow. This review delineates how GoC technology is advancing oral drug delivery by bridging biology, microengineering, and pharmacology. We summarize advances across three therapeutic domains-small-molecule drugs, macromolecular and biopharmaceutical agents, and microbiome-interacting therapeutics-highlighting how GoCs now recapitulate absorption, enzymatic metabolism, immune modulation, and microbial transformation in human-relevant contexts. By merging organ-level physiology with analytical precision, GoCs establish a unified platform for predicting oral bioavailability and systemic exposure. As these systems evolve toward sensor-integrated, multi-omics, and AI-enabled designs, they are poised to become the mechanistic backbone of next-generation preclinical drug discovery and personalized oral therapeutics.