Modular design for drug delivery across hierarchical gastrointestinal barriers: From materials to systems

Drug delivery to the gastrointestinal (GI) tract necessitates overcoming multi-level physiological barriers from organ to cellular levels, which exhibit significant heterogeneity under pathological conditions. Conventional delivery strategies, constrained by single-function capabilities, struggle to achieve cross-scale coordination, severely limiting therapeutic efficacy. Modular design (MD) offers an innovative approach to synergistically breaching multiple barriers by decoupling complex functions into standardized units and enabling intelligent assembly. This review systematically analyzes the characteristics and delivery challenges of each barrier level within the GI tract, establishing a materials library that encompasses functional modules for organ-level regulation, mucosal penetration, cellular delivery, and environmental responsiveness. Utilizing GI inflammation and infection as exemplars, the text goes on to highlight the mechanisms and applications of modular assembly strategies in achieving breakthroughs in organ-mucosa, organ-cell, and full-layer barrier technologies. Additionally, it assesses the challenges and prospects for clinical translation. This paper aims to provide design strategies for developing next-generation intelligent oral delivery systems capable of spatiotemporal programming and dynamic response to the multi-level barriers and pathological microenvironments of the digestive tract. This should drive a paradigm shift towards precise drug delivery within complex physiological settings.