Inspired by the survival strategies of pyomelanin-producing microbes, we synthesize pyomelanin nanoparticles (PMNPs) from homogentisic acid- gamma-lactone via auto-oxidation and investigate their biomedical potential. PMNPs possess distinct physicochemical properties, including reactive oxygen species scavenging and microenvironment-responsive self-disassembly. Under intestinal conditions, PMNPs self-disassemble and penetrate the nanoscale pores of the mucin layer. In an inflammatory bowel disease model, orally administered PMNPs withstand gastric acidity and, in their solubilized form, interact with macrophages and epithelial cells. They significantly reduce reactive oxygen species levels, exert anti-inflammatory effects, and restore gut microbiota composition. Compared to conventional nanoparticles and 5-aminosalicylic acid, PMNPs exhibit greater therapeutic efficacy. Clinical symptoms and intestinal inflammation are alleviated, and the gut microbiota is restored to near-normal levels. These findings underscore the therapeutic potential of PMNPs for inflammatory bowel disease treatment and suggest broader biomedical applications.