Andrias Davidianus Peptide Hydrogel Enables Sustained SR9011 Release to Promote Efferocytosis and Alleviate Colitis

Abstract Ulcerative colitis (UC) is a chronic inflammatory disorder marked by epithelial barrier disruption and defective resolution of inflammation. Although epithelial apoptosis and impaired efferocytosis are recognized contributors to disease progression, their molecular regulation remains insufficiently defined. NR1D1, a circadian transcriptional repressor implicated in immune control, has not been fully explored in UC. Here, this study shows that NR1D1 expression is markedly reduced in human UC biopsies and murine colitis. CUT&Tag profiling revealed direct NR1D1 chromatin occupancy, while ChIP–qPCR and luciferase assays confirmed that NR1D1 represses CD47, a key anti‐efferocytosis molecule. Functional experiments demonstrate that NR1D1 deficiency enhances epithelial apoptosis, upregulates CD47, impairs macrophage efferocytosis, and exacerbates colitis in IEC‐specific Nr1d1 −/− mice. To restore NR1D1 activity, a hydrogel (HA@Alg‐ADAP‐SR9011) combining Andrias davidianus peptides is engineered with the NR1D1 agonist SR9011 for targeted, sustained intestinal delivery. In DSS‐induced colitis, hydrogel‐mediated SR9011 suppresses inflammation, reduces CD47, preserves epithelial integrity, and improves histological outcomes. Single‐cell RNA sequencing further reveals reduced CD47 and enhances efferocytic signatures in SR9011‐treated tissues. While pharmacokinetic analyses are limited to colonic tissue, these findings establish NR1D1 as a central regulator of epithelial turnover and efferocytosis in UC and support hydrogel‐based NR1D1 activation as a therapeutic strategy.