Ameliorating macrophage pyroptosis via ANXA1/NLRP3/Caspase-1/GSDMD pathway: Ac2-26/OGP-loaded intelligent hydrogel enhances bone healing in diabetic periodontitis

作者：Ruoyu Li, Wenfeng Li, Yungshan Teng, Runze Li, Siyi Kong, Xin Chen, Haotian Luo, Danying Chen, Yuqing Guo, Ying Qing, Hio Cheng Leong, Bingyan Guo, Meihan Chen, Zixin Pan, Shushuo Zheng, Yihong Deng, Cao Yang, Chen Zhou, Xuenong Zou, Weicai Wang · 发表于：Biofabrication · 年份：2025 · DOI：10.1088/1758-5090/ada737 · 被引用次数：16 · 研究领域：Inflammasome and immune disorders、Oral microbiology and periodontitis research、Advanced Glycation End Products research

Craniofacial bone defect healing in periodontitis patients with diabetes background has long been difficult due to increased blood glucose levels which cause overproduction of reactive oxygen species (ROS) and a low pH environment. These conditions negatively affect the function of macrophages, worsen inflammation and oxidative stress, and ultimately, hinder osteoblasts' bone repair potential. In this study, we for the first time found that annexin A1 (ANXA1) expression in macrophages was reduced in a diabetic periodontitis (DP) environment, with the activation of the NLRP3/Caspase-1/GSDMD signaling pathway, and, eventually, increased macrophage pyroptosis. Next, we have developed a new GPPG intelligent hydrogel system which was ROS and pH responsive, and loaded with Ac2-26, an ANXA1 bioactive peptide, and osteogenic peptide OGP as well. We found that Ac2-26/OGP/GPPG can effectively reduce ROS, mitigates macrophage pyroptosis via the ANXA1/NLRP3/Caspase-1/GSDMD pathway and enhanced osteogenic differentiation. The effect of Ac2-26/OGP/GPPG in regulation of pyroptosis and bone defect repair was also further validated by animal experiments on periodontitis-induced tooth loss model in diabetic rats. To conclude, our study unveils the effect of ANXA1 on macrophage pyroptosis in periodontitis patients with diabetes, based on which we introduced a promising innovative hydrogel system for improvement of bone defects repair in DP patients via targeting macrophage pyroptosis and enhanc...