Stiffness-dependent CMOT hydrogels promote mucosal repair in ulcerative colitis through YAP‑mediated mechanosensing in intestinal epithelial cells.

In this study, a series of mechanically tunable CMOT hydrogels was successfully developed, which enable colon‑targeted delivery and controlled degradation via dynamic Schiff‑base cross‑linking. Among them, the moderately stiff CMOT‑M hydrogel best mimics the native mechanical microenvironment of intestinal tissue, significantly alleviating DSS‑induced colitis symptoms, restoring the expression of tight‑junction proteins (ZO‑1, occludin), and suppressing excessive production of inflammatory cytokines (TNF‑α, IL‑6, IL‑1β). Mechanistic investigations revealed that the CMOT‑M hydrogel modulates the Hippo signaling pathway through integrin‑cytoskeletal tension transmission, thereby precisely tuning the phosphorylation status and nuclear translocation of YAP/TAZ: during the acute phase, it moderately activates YAP/TAZ to promote epithelial proliferation and migration; during the repair phase, it suppresses excessive YAP/TAZ activation, guiding stem‑cell differentiation and preventing fibrosis. After loading with the herbal formula QCXPY (CMOT@QCXPY), the hydrogel further synergistically inhibits the IL‑6/STAT3 pathway and reshapes the gut microbiota, establishing a multidimensional regulatory network integrating mechanical, immune, and microbial cues. This work demonstrates that material stiffness serves as a critical design parameter that can promote mucosal regeneration through YAP‑mediated mechanosensing, offering a novel mechano‑therapeutic strategy for ulcerative colitis.