Inflammatory bowel disease (IBD) is driven by barrier dysfunction, microbiome dysbiosis, and aberrant immune responses. Although methylprednisolone (MPS) is effective for immunosuppression, it disrupts the intestinal barrier and causes severe systemic toxicity,limiting long-term use. To address these issues, we developed MPS-loaded hyaluronic acid–bilirubin nanoparticles (MPS@HABN), an oral nanomedicine that reduces toxicity while enhancing gut microbiome-modulating and anti-inflammatory activities. HABN selectively targets inflamed colon via the HA shell and enables reactive oxygen species (ROS)-responsive MPS release through the bilirubin core, minimizing premature drug leakage. In DSS-induced colitis, MPS@HABN synergistically modulated microbiome and immune responses, while HABN itself reinforced epithelial barrier and mitigated MPS-induced damage. Overall, these effects disrupted the pathological cycle linking barrier, microbiome, and immune dysfunction, achieving strong therapeutic efficacy. Thus, MPS@HABN represents a promising and translatable platform for safe and effective IBD therapy.