Barrier-reinforcing hyaluronic acid-bilirubin nanodelivery of methylprednisolone for synergistic modulation of the intestinal barrier, immune system, and gut microbiome in colitis.

Inflammatory bowel disease (IBD) is characterized by a self-reinforcing cycle of intestinal barrier dysfunction, gut microbiome dysbiosis, and aberrant mucosal immune responses. Methylprednisolone (MPS) is a potent immunosuppressant used for IBD and may beneficially modulate the gut microbiome, but its systemic adverse effects and potential impairment of epithelial repair limit its therapeutic use. To overcome these limitations, we developed MPS-loaded hyaluronic acid-bilirubin nanoparticles (MPS@HABN), an oral nanomedicine designed to protect the intestinal epithelium from MPS-associated injury while enhancing the otherwise limited immune and microbiome modulation achieved by low-dose HABN. MPS@HABN limited premature drug release, increased MPS accumulation in the inflamed colon, and reduced systemic exposure and thymic involution. It also protected intestinal epithelial cells from MPS-associated and oxidative injury. In contrast, low-dose HABN alone showed limited immune and microbiome modulation, whereas free MPS caused intestinal barrier damage and systemic toxicity such as thymic involution. In a DSS-induced colitis model, MPS@HABN improved intestinal barrier function while enhancing immune and microbiome modulation, resulting in robust therapeutic efficacy beyond that of either component alone at a low HABN dose and a clinically relevant MPS dose. These findings support combining the complementary activities of MPS and HABN to overcome corticosteroid-associated epithelial injury and the limited efficacy of low-dose HABN, thereby helping to disrupt the pathological barrier-immune-microbiome cycle in colitis.