Synthetic Antibody Mimetics with ROS-Gated Saccharide Release for Targeted Colitis Therapy.

Conventional targeted therapies for inflammatory bowel disease (IBD) often rely on unstable biological recognition elements. While molecularly imprinted polymers (MIP) offer robust synthetic alternatives, their utility is limited by an "always-on" binding state: even weak non-specific adsorption can significantly compromise their target-binding capacity. We convert static MIP into reactive oxygen species (ROS)-activated therapeutic actuators by conjugating mannose to transferrin-imprinted MIP via a ROS-cleavable linker. The saccharide acts dually as a therapeutic agent and a protective cloak. It sterically blocks non-specific binding during intestinal transit. At inflammatory sites, elevated ROS levels (higher than in healthy tissue) trigger simultaneous mannose release and activation of high-affinity targeting. This enables precise MIP anchoring to the inflamed epithelium for physical barrier formation and localized microbiome modulation. In murine colitis models, this achieved mucosal healing, mitigated inflammation, and microbiota rebalancing using a mannose equivalent dose of 27.2 mg/kg/d, benchmarking against free mannose and non-responsive MIP controls. This work establishes a generalizable paradigm for targeted recognition and drug delivery in complex physiological environments, paving the way for intelligent, disease-responsive nanomedicines.