Dual‐Scale Targeting of Myofibroblasts and Mitochondria via Oral Cascade Delivery Systems Alleviate Intestinal Fibrosis

ABSTRACT Conventional anti‐inflammatory agents fail to effectively treat intestinal fibrosis in inflammatory bowel disease (IBD) due to distinct pathological mechanisms. Myofibroblast activation and mitochondrial dysfunction are central drivers linking fibrosis and inflammation, which require precise drug delivery to both the cellular and subcellular levels. Herein, we introduce an oral cascade‐targeted drug delivery system with “cell‐organelle dual‐scale targeting”, aiming to direct one therapeutic component targeting myofibroblasts and another targeting mitochondria. This system overcomes physiological barriers through a three‐tiered strategy: 1) inulin gel‐based mucosal adhesion for colon delivery; 2) myofibroblast‐targeted delivery of antifibrotic agent simvastatin via fibronectin‐binding; 3) mitochondrial‐targeted delivery of antioxidant resveratrol in various fibrosis‐associated cells mediated by mitochondrial targeting sequence (MTS). The platform exhibited anti‐inflammation in macrophages, mucosal repairing in epithelial cells, and antifibrotic activity in myofibroblasts. In vivo studies further demonstrated that, on the basis of mitochondrial‐targeted anti‐inflammatory therapy, additional inhibition of myofibroblast activation effectively alleviated collagen deposition and gut thickening. This research provides insight into the effective treatment of IBD‐associated intestinal fibrosis.