Colitis-associated colorectal cancer (CAC) arises from the vicious circle of inflammation, metabolic disorder, and gut microbiota dysbiosis, and further contributes to disease progression and systemic complications, including neurological function disruptions via the microbiota-gut-brain axis (MGBA). Current therapies fail to address multiple pathological processes. Here, an oral administration-friendly Twin-Drink therapy was designed to rapidly gel in the stomach upon sequential ingestion, protecting and delivering BNBZ-loaded nanoparticles (PHC NP) and the anthocyanin Cy3G. This system enables alkaline/ROS dual-response release in the microenvironment of colon inflammation. Released PHC NP inhibits tumor growth by blocking glycolysis and inducing apoptosis; Cy3G exerts anti-inflammatory and microbiota remodeling effects. Twin-Drink demonstrated successful endogastric gelation in a preliminary Beagle study. In the CAC mouse model, Twin-Drink significantly reduced inflammation, restored colon length, and inhibited tumor occurrence. Moreover, Twin-Drink enriched beneficial bacteria (e.g., Muribaculaceae), restored microbiota-associated metabolic homeostasis, and correlated with marked improvements in MGBA-mediated behavioral deficits. This study presents a drinkable, precision delivery platform for CAC management.
