Montmorillonite@Metal oxide nanocomposites enables multitarget therapy for inflammatory bowel disease treatment.

INTRODUCTION: Inflammatory bowel disease (IBD) is a global health challenge characterized by excessive reactive oxygen species (ROS) accumulation, immune dysregulation, and impaired intestinal barrier integrity. Although montmorillonite (MMT) is clinically used for gastrointestinal protection, its limited anti-inflammatory and ROS-scavenging activities restrict its therapeutic potential in intestinal inflammatory disorders. OBJECTIVES: This study aimed to develop a multifunctional clay-supported nanozyme platform and evaluate its therapeutic effects in dextran sulfate sodium (DSS)-induced acute colitis model through the rational construction and screening of MMT-supported metal oxide nanocomposite (MMT@MxOy) library. METHODS: A library of MMT@MxOy was constructed by integrating different metal oxide nanozymes onto MMT. The nanocomposites were screened and optimized by electron-transfer behavior, multienzyme-mimetic activities, and ROS-scavenging performance. Therapeutic efficacy was evaluated in DSS‑induced acute colitis model. Therapeutic mechanisms were investigated using transcriptomic profiling, gut microbiota analysis, biochemical assays, and molecular validation. RESULTS: MMT@MnO2 was identified as the leading nanocomposite owing to favorable electron-transfer characteristics and enhanced loading-normalized multienzyme-mimetic and ROS scavenging activities. Optimizing Mn precursor feeding ratio produced the lead MMT@MnO2 formulation, which exhibited favorable biocompatibility. In vivo, MMT@MnO22 alleviated body weight loss, reduced disease activity, preserved colon length, attenuated histopathological injury, and promoted mucus barrier recovery. Improvements in disease-related indices approached the orally administered 5-aminosalicylic acid, although route differences preclude direct pharmacological comparison. Mechanistically, MMT@MnO2 attenuated oxidative stress and inflammatory responses, promoted macrophage phenotype remodeling toward less inflammatory and more reparative state, restored epithelial tight junction, and partially recovery of gut microbial homeostasis. Transcriptomic analysis and downstream molecular validation supported the involvement of NF-κB-related inflammatory suppression, phagosome-associated immune remodeling, and Rap1/ERK-related epithelial repair. CONCLUSION: This work established a rational design framework for clay-based nanotherapeutics and identified MMT@MnO2 as a promising multitarget platform for alleviating DSS-induced acute colitis, offering a basis for future translational development of local nanotherapeutic strategies for intestinal inflammatory diseases.