Construction of a MOF‐Based Snap‐Top Delivery Nanosystem for Powerful Dual‐Responsive Synergistic Colitis Treatment

ABSTRACT Oral treatment of inflammatory bowel disease (IBD) faces significant challenges of poor targeting, low bioavailability, and systemic toxicity, necessitating intelligent stimuli‐responsive delivery systems. Here, we design and synthesize a pH/hypoxia dual‐responsive pendant azobenzene‐functionalized MOF (Azo‐MOF). The uniformly distributed azobenzene pendants serve as intrinsic gating sites, forming “snap‐top” encapsulation with β‐cyclodextrin through host‐guest interactions that prevent premature 6‐mercaptopurine leakage while enabling rapid stimuli‐triggered release, creating a postmodification‐free supramolecular gated delivery nanosystem (CAMM). CAMM exhibits hypoxia‐triggered burst release and alkaline‐sustained release, with <5.0% drug leakage during gastrointestinal transit and >90.0% cumulative release at inflammatory sites. Notably, the Azo‐MOF carrier scavenges reactive oxygen species through synergy between its conjugated π ‐system and metal coordination environment, providing antioxidant protection alongside drug delivery. In dextran sulfate sodium‐induced colitis models, CAMM outperformed free drug, achieving near‐complete weight recovery, downregulating proinflammatory cytokines, restoring intestinal barrier integrity, and rebalancing gut microbiota by enriching Lactobacillus and Bifidobacterium while suppressing opportunistic pathogens. This study integrates targeted delivery, antioxidant therapy, and microbiota modulation, offering an effective strategy for precision IBD treatment.