Yeast-Inspired Orally-Administered Nanocomposite Scavenges Oxidative Stress and Restores Gut Immune Homeostasis for Inflammatory Bowel Disease Treatment

Excessive oxidative stress, dysregulated immune homeostasis, and disruption of the intestinal epithelial barrier are crucial features of inflammatory bowel disease (IBD). Traditional treatments focusing solely on inflammation resolution remain unsatisfactory. Herein, a yeast-inspired orally administered nanocomposite was developed. First, the MD@MPDA core was fabricated by integrating manganese dioxide (MnO 2 ) nanozymes onto diallyl trisulfide (H 2 S prodrug)-loaded mesoporous polydopamine nanoparticles (MPDA). Then, yeast cell wall (YCW) was chosen to encapsulate MD@MPDA, namely, YMD@MPDA. The β-glucan embedded in the YCW shell not only protected the nanocomposite from the harsh gastrointestinal environment but also allowed the targeting enrichment in the inflamed colon. Furthermore, M1 macrophages triggered the intracellular GSH-responsive H 2 S release in the pathological microenvironment. MD@MPDA effectively alleviated inflammatory responses by MnO 2 -mediated ROS-scavenging and H 2 S-participated immunomodulation. The synergistic action contributed to macrophage mitochondrial function restoration and M2 polarization by suppressing NOX4 signaling and p38 MAPK pro-inflammatory signaling. In the mice model of dextran sulfate sodium (DSS)-induced IBD, the multipronged manner of scavenging oxidative stress, remodeling innate and adaptive immune homeostasis, and reshaping gut microbiota caused by YMD@MPDA effectively ameliorated inflammation and restored intestinal barrier functions. Overall, the YMD@MPDA nanocomposite provides a promising codelivery strategy of antioxidative nanozymes and gas prodrugs for the comprehensive management of IBD.