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20 reviewsInspired by the survival strategies of pyomelanin-producing microbes, wesynthesize pyomelanin nanoparticles (PMNPs) from homogentisic acid- γlactone via auto-oxidation and investigate their biomedical potential. PMNPspossess distinct physicochemical properties, including reactive oxygen species scavenging and microenvironment-responsive self-disassembly. Underintestinal conditions, PMNPs self-disassemble and penetrate the nanoscalepores of the mucin layer. In an inflammatory bowel disease model, orallyadministered PMNPs withstand gastric acidity and, in their solubilized form,interact with macrophages and epithelial cells. They significantly reducereactive oxygen species levels, exert anti-inflammatory effects, and restore gutmicrobiota composition. Compared to conventional nanoparticles and5-aminosalicylic acid, PMNPs exhibit greater therapeutic efficacy. Clinicalsymptoms and intestinal inflammation are alleviated, and the gut microbiota isrestored to near-normal levels. These findings underscore the therapeuticpotential of PMNPs for inflammatory bowel disease treatment and suggestbroader biomedical applications.