Anti‐Inflammatory Mechanisms of Selenium Nanosheets in Ulcerative Colitis: Protein Corona, GP130 Interaction, and Transcriptomic Profile

Abstract Ulcerative colitis (UC) is a complex inflammatory bowel disease characterized by multiple factors. Alleviating inflammation is the primary therapeutic approach. However, currently employed anti‐inflammatory treatments have limited efficacy and cause side effects. Safer, more effective therapies are needed. Selenium nanosheets (SeNSs) are biocompatible, anti‐inflammatory, and low‐toxicity nanomaterials with high surface areas and abundant active sites, making them potential therapeutic agents for UC. This study indicates that SeNSs can interact with macrophages and adhere to their cell membranes, significantly increasing their internalization into cells. Proteomic analysis reveals that the main components of the SeNS protein corona are proteins involved in cell proliferation and migration, including those associated with the AKT/PI3K and NF‐κB signaling pathways. SeNSs hydrophobically interact with GP130, inhibiting its expression. This interaction downregulates the proteins involved in the aforementioned pathways. In addition, a transcriptomic analysis confirms that SeNSs inhibit apoptosis, cytokine–cytokine receptor interactions, and the chemokine and TNF signaling pathways. In dextran sulfate sodium (DSS)‐induced UC model mice, SeNSs significantly decrease IL‐1β, IL‐6, and TNF‐α levels, alleviate tissue damage, and lower the disease activity index. These findings suggest that SeNSs can be a safe and effective treatment strategy for UC, offering a novel approach for managing inflammatory diseases.