Carrier‐Free Nanocapsule with Dual‐Target Capacity for Synergistically Restoring Inflammatory Microenvironment and Microbiota Dysbiosis in Colitis

Abstract Inflammatory bowel disease (IBD) is a chronic inflammatory disease with limited therapeutic outcomes. Macrophages are the key gatekeepers of intestinal immune homeostasis and have vital influence on IBD. Hence, macrophages are recognized as attractive targets to develop new therapeutic. However, the therapy development has proven challenging due to the malignant biological chain between macrophage immune hyperresponsiveness and dysbiosis of intestinal microflora. Herein, a carrier‐free nano‐drug, PCNPs@PEG‐Man, with dual‐targeting function, is produced due to IBD lesion‐specific positive charge and high expression of mannose receptor. With super resistance against extreme intraluminal conditions, PCNPs@PEG‐Man showes stable ROS‐scavenging properties thereby. Notably, the dual‐targeting strategy enhances the endocytosis efficiency and intestinal retention time of the drug, which is conducive to the downregulation of pro‐inflammatory factors, upregulation of anti‐inflammatory factors, and repair of the intestinal barrier. Additionally, it reshaped the dysbiosis of intestinal bacteria, revealing an optimized gut flora composition of probiotics. The mechanism of the carrier‐free nano‐drug mainly involves the elimination of oxidative stress, promoting macrophage M2 polarization, and restoring gut homeostasis. The synergistic effect inherent in this dual‐targeting system presents an effective and safe approach to managing IBD, providing new insights into the treatment of intestinal ROS‐mediated diseases associated with microbiota dysbiosis.