Squid-ink-derived eumelanin nanoparticles improve glycaemic control through gut-centered metabolic remodeling in type 2 diabetes.

Type 2 diabetes (T2D) is increasingly recognized as a systemic metabolic disorder in which intestinal dysfunction contributes to multi-organ metabolic imbalance. Here we show that orally administered squid-ink-derived eumelanin nanoparticles (EmNPs) ameliorate hyperglycaemia and tissue injury in diabetic mice. Structural analyses confirmed that EmNPs retain the characteristic indole/quinone framework, stable radical properties and nanoscale self-assembled architecture of natural eumelanin. In vivo, EmNPs lowered fasting blood glucose, improved an FST-based depression-related behavioral readout, and improved histopathological injury in the small intestine, pancreas and hippocampus. To investigate the basis of these effects, we integrated gut microbiota profiling, intestinal transcriptomics, untargeted urinary metabolomics and targeted hepatic energy-metabolite analysis. EmNPs treatment was associated with partial correction of diabetes-associated gut microbial dysbiosis and was accompanied by intestinal transcriptional remodeling centred on epithelial/barrier function, amino acid metabolism, PPAR-related pathways and bile-acid-associated programs. These intestinal changes were associated with broad correction of urinary metabolic abnormalities involving amino acid, purine and energy metabolism. Targeted hepatic metabolite profiling further revealed EmNPs-associated remodeling of glycolysis- and TCA-related steady-state metabolite abundance. Together, these findings support an association-based, gut-centered model in which changes in the intestinal metabolic milieu are associated with systemic metabolic normalization, hepatic energy-metabolite remodeling, and improved glycaemic control in T2D.