Multifactorial interactions involved pro -inflammatory microenvironment plays a crucial role in ulcerative colitis initiation and progression. Oral nanozymes hold great promise in ameliorating inflammation attributing to their enzyme mimesis -mediated oxidative stress regulation capabilities. However, the development of biocompatible, gastrointestinal well -tolerant, and multi -enzyme mimetic antioxidant nanomedicine is highly desirable but challenging. Here, inspired by natural occurring fungal allomelanin, intrinsically bioactive allomelanin-like nanomedicine (alloMel) were fabricated as a safe and effective formulation for re-educating the intestinal proinflammatory microenvironment in colitis. The as-preapared alloMel possessed satisfactory biocompatibility, hydrogen peroxide -triggered decomposition behavior, broad-spectrum free radical scavenging capacities and specific targeting ability toward the colitis lesions. More importantly, alloMel exhibited favorable tolerance against the harsh gastrointestinal environment, evidenced by structural and property stability assay in simulated gastric fluid and simulated intestinal fluid. Following oral administration into dextran sulfate sodium -induced acute colitis mice, alloMel exhibited superior therapeutic efficacy than that of 2.5 -fold dose of the first -line drug 5-aminosalicylic acid, evidenced by reversed body weight loss, decreased disease activity index, restrained colon length shortening, and mitigatory histopathological abnormalities. Mechanistically, alloMel ameliorated the self-perpetuating pro -inflammatory microenvironment by combined actions including alleviating oxidative stress, reducing the production of pro -inflammatory cytokines, restraining inflammatory cell infiltration, switching macrophage phenotype, and restoring intestinal barrier integrity. Molecularly, alloMel could inhibit the TLR4/MyD88/NF-& kcy;B signaling pathway. In conclusion, the as -reported alloMel with favorable gastrointestinal tolerance and well -elucidated mechanisms represents a potential translational nanomedicine against colitis and oxidative stress -associated other gastrointestinal inflammatory disorders.