Anion‐Dependent Layered Double Hydroxide Nanoparticles Regulate Differentiation of CD206⁺ CX3CR1⁺ Macrophages by Inhibiting the IL‐17 Signaling Pathway Contributing to Inflammatory Bowel Disease

Abstract Inflammatory bowel disease (IBD) is a chronic and destructive autoimmune disease that has created a global burden. However, the pathogenesis and treatment strategies of IBD remain difficult problems to overcome. The anti‐inflammatory action of anion‐dependent layered double hydroxide (LDH) is evaluated in IBD. Raw264.7 macrophages induced by Lipopolysaccharide (LPS) produced low levels of pro‐inflammatory cytokines after LDH treatment. The results from dextran sulfate sodium (DSS)‐induced murine colitis models show that LDHs significantly reduce pro‐inflammatory cytokines in the colon tissue and inhibit colon atrophy. Most importantly, LDH with NO₃⁻ as the interlayer anion (LDH‐NO₃⁻) demonstrates superior anti‐inflammatory ability compared to LDH with Cl⁻ as the interlayer anion (LDH‐Cl⁻), both in vitro and in vivo. LDH‐NO₃⁻ promotes the differentiation of CD206⁺CX3CR1⁺ lamina propria macrophages, reduces the abundance of T helper 17 (Th17) cells, and inhibits the activation of the IL‐17 signaling pathway. LDH‐NO₃⁻ also limits the pro‐inflammatory effects of IL‐17A on macrophages, and the anti‐inflammatory effects of LDH‐NO₃⁻ are reversed by IL‐17RA‐siRNA. Suggesting that LDH effectively inhibits the inflammatory reaction induced by the interaction between macrophages and Th17 cells. This study demonstrates that LDH‐NO₃⁻ is a drug‐free nanomedicine that acts against IBD, providing application prospects for LDH‐NO₃⁻ in IBD treatment.