Abstract

Inflammatory bowel disease (IBD) remains a therapeutic challenge due to its ongoing inflammation and the limited availability of effective local therapies. This study developed a biomimetic nanocomposite, layered double hydroxide-molybdenum disulfide (LDH-MoS2 [LM]) nanosheets encapsulated with bovine serum albumin (abbreviated as LM@BSA), with the aim of enhancing reactive oxygen species scavenging efficiency and improving colloidal stability while favoring lesion-associated localization and local retention in inflamed colonic tissue. In a dextran sulfate sodium-induced colitis mouse model, oral administration of LM@BSA nanocomposite significantly improved disease outcomes, as shown by reduced colon shortening, less body weight loss, and decreased levels of pro-inflammatory cytokines. Mechanistic analysis demonstrated that the LM@BSA nanocomposite inhibits ferroptosis by protecting mitochondrial structure and increasing glutathione peroxidase 4 expression. Transcriptomic data showed that the LM@BSA nanocomposite helps restore intestinal balance by down-regulating the phosphoinositide 3-kinase–protein kinase B signaling pathway, regulating extracellular matrix remodeling, and supporting immune pathway stability. Moreover, the LM@BSA nanocomposite corrected gut microbiota dysbiosis by increasing the abundance of beneficial Bacteroidales and reducing pro-inflammatory Desulfovibrionales. These findings suggest that the LM@BSA nanocomposite offers a promising and comprehensive multifaceted nanotherapeutic approach for IBD by modulating oxidative stress, ferroptosis, immune dysregulation, and gut microbiota imbalance.