Post‐translational modifications in intestinal epithelial cells (IECs) allow for precise control in intestinal homeostasis, the breakdown of which may precipitate the pathological damage and inflammation in inflammatory bowel disease. The O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) modification on intracellular proteins controls diverse biological processes; however, its roles in intestinal homeostasis are still largely unexplored. Here, we found that levels of protein O‐GlcNAcylation and the expression of O‐GlcNAc transferase (OGT), the enzyme adding the O‐GlcNAc moiety, were reduced in IECs in human IBD patients. Deletion of OGT specifically in IECs resulted in disrupted epithelial barrier, microbial dysbiosis, Paneth cell dysfunction, and intestinal inflammation in mice. Using fecal microbiota transplantation in mice, we demonstrated that microbial dysbiosis although was insufficient to induce spontaneous inflammation but exacerbated chemical‐induced colitis. Paneth cell‐specific deletion of OGT led to Paneth cell dysfunction, which might predispose mice to chemical‐induced colitis. On the other hand, the augmentation of O‐GlcNAc signaling by inhibiting O‐GlcNAcase, the enzyme removing O‐GlcNAcylation, alleviated chemical‐induced colitis. Our data reveal that protein O‐GlcNAcylation in IECs controls key regulatory mechanisms to maintain mucosal homeostasis.

Drug resistance is the major challenge facing cancer chemotherapy and nanoscale delivery systems based on natural materials, such as sericin, are a promising means of overcoming drug resistance. Yet, no attempt of introducing synthetic poly(γ-benzyl-L-glutamate) (PBLG) onto sericin polypeptide to fabricate a facile biocompatible and biodegradable micelle has been tried. Here, we prepared a polypeptide-based amphiphilic polymer containing hydrophilic sericin polypeptide backbone and PBLG side chains via ring-opening polymerization (ROP) strategy. The introduction of PBLG side chains remarkably enhances the stability of sericin micelles in water. Meanwhile, the micelles exhibited a high loading capacity and pH-responsive release ability for antitumor drug doxorubicin (DOX), called sericin-PBLG-DOX. Owing to the excellent cell membrane penetration of sericin-PBLG, the cellular uptake of DOX when loaded into micelles was improved. Subsequently, sericin-PBLG-DOX was transferred into perinuclear lysosomes, where the release rate of DOX was accelerated. Compared to the same dose of DOX, sericin-PBLG-DOX could induce a more efficient anti-tumor effect both in vitro and in vivo, and these micelles have promise for future clinical applications in overcoming cancer drug resistance with good biosafety, enhanced cellular uptake, pH-triggered drug release, efficient anti-tumor effects, and minimized systemic toxicity.

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