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Here, leveraging single\u2010cell RNA sequencing (scRNA\u2010seq) technology, the pivotal role of nitric oxide (NO) and reactive oxygen species (ROS) is unveiled in impeding macrophage repolarization during physiological bone remodeling amidst diabetes. Guided by scRNA\u2010seq analysis, we engineer a multienzymatic bone tissue engineering hydrogel scaffold (MEBTHS) composed is engineered of methylpropenylated gelatin hydrogel integrated with ruthenium nanozymes, possessing both Ru\n                    <jats:sup>0<\/jats:sup>\n                    and Ru\n                    <jats:sup>4+<\/jats:sup>\n                    components. This design facilitates efficient NO elimination via Ru\n                    <jats:sup>0<\/jats:sup>\n                    while simultaneously exhibiting ROS scavenging properties through Ru\n                    <jats:sup>4+<\/jats:sup>\n                    . Consequently, MEBTHS orchestrates macrophage reprogramming by neutralizing ROS and reversing NO\u2010mediated mitochondrial metabolism, thereby rejuvenating bone marrow\u2010derived mesenchymal stem cells and endothelial cells within diabetic mandibular defects, producing newly formed bone with quality comparable to that of normal bone. The scRNA\u2010seq guided multienzymatic hydrogel design fosters the restoration of self\u2010regenerative repair, marking a significant advancement in bone tissue engineering.\n                  <\/jats:p>","DOI":"10.1002\/adma.202410962","type":"journal-article","created":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T08:56:43Z","timestamp":1729587403000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["A Single\u2010Cell RNA Sequencing Guided Multienzymatic Hydrogel Design for Self\u2010Regenerative Repair in Diabetic Mandibular Defects"],"prefix":"10.1002","volume":"36","author":[{"given":"Peihua","family":"Lin","sequence":"first","affiliation":[{"name":"Frontiers Science Center for Transformative Molecules School of Chemistry and Chemical Engineering School of Biomedical Engineering National Center for Translational Medicine Zhang Jiang Institute for Advanced Study Shanghai Jiao Tong University  Shanghai 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