Acute radiation enteritis (ARE) commonly limits escalation during abdominopelvic radiotherapy, and conventional therapies are ineffective in reversing tissue damage. This study introduces EcN_Tyr, a genetically engineered probiotic created through a synthetic biology-nanomedicine approach. Based on the clinical-grade probiotic Escherichia coli Nissle 1917 (EcN), this strain integrates three core functional modules through comprehensive engineering. By knocking out the genes of chorismate competitive pathways (ΔpheA/ΔtrpR/ΔpykA) and optimizing codon expression for tyrosinase, melanin could be effectively biosynthesized in situ in the intestinal tract. Targeted colonization facilitated by F1 fimbriae, along with the covalent binding of melanin quinones to mucin, increased EcN_Tyr adhesion to the inflamed lesions by fourfold over wild-type EcN and achieved prolonged local retention. In murine ARE models, EcN_Tyr demonstrated a therapeutic effect by mitigating oxidative stress and inflammation (by modulating IL-6, tumor necrosis factor-α (TNF-α)), restoring gut microbiota composition (by enriching Bacteroidetes/Akkermansiaceae, reducing pathogenic Proteobacteria), and regulating genes associated with intestinal repair. Transcriptome analysis further demonstrated that EcN_Tyr treatment reprogrammed intestinal gene expression profiles, attenuating inflammation-associated signaling while restoring metabolic and redox homeostasis programs. This "colonization-synthesis-repair" system addresses conventional probiotic limitations, offering a safe, efficient, and translatable precision therapy for radiation-induced tissue injury.