Trojan horse-inspired smart single-atom nanozyme delivery system for synergistic therapy of inflammatory bowel disease

Systemic administration for the clinical management of inflammatory bowel disease (IBD) often leads to various side effects and toxicities, primarily due to broad therapeutic exposure of non-target tissues. Herein, a smart single-atom nanozyme (SAzymes) delivery system (Fe–SA/Cur@HAD, FCH) is constructed through coordinating iron-doped SAzymes (Fe–SA) with curcumin (Cur) for IBD synergistic therapy. Inspired by Trojan horse, FCH efficiently responds to the IBD pathological microenvironment and realizes targeted delivery via oral administration. In inflamed colonic tissue, FCH regulates redox homeostasis through the superoxide dismutase (SOD)-catalase (CAT) cascade reaction and releases Cur by changing the adsorption energy, thus achieving synergistic therapy. An in vitro IBD model of human-derived colonic organoid, along with in vivo IBD model of mouse, were used and demonstrated that this system could effectively reduce reactive oxygen species (ROS) levels, improve intestinal homeostasis, and promote tissue recovery. Additionally, FCH markedly suppresses the activation of inflammatory pathways and modulates the composition of the intestinal microbiota. This study innovatively modifies SAzymes, offering new perspectives on their potential applications in IBD treatment. A single-atom nanozyme delivery system is constructed for inflammatory bowel disease synergistic therapy by reducing cell apoptosis, promoting intestinal barrier function, inhibiting inflammation-related pathways, and restoring the homeostasis of gut microbiota.