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Hydrogel has emerged as a type of viable substitute, but its inhomogeneous networks and weak mechanics greatly impede clinical applications. Here, a dual crosslinked gelling system is developed with tunable architectures and mechanics to promote osteogenic capacity. Polyhedral oligomeric silsesquioxane (POSS) is designated as a rigid core surrounded by six disulfide\u2010linked PEG shells and two 2\u2010ureido\u20104[1H]\u2010pyrimidinone (UPy) groups. Thiol\u2010disulfide exchange is employed to fabricate chemical network because of the pH\u2010responsive \u201con\/off\u201d function. While self\u2010complementary UPy motif is capable of optimizing local microstructure to enhance mechanical properties. Taking the merits of biocompatibility and high\u2010mechanics in periodontal ligament stem cells (PDLSCs) proliferation, attachment, and osteogenesis, hybrid hydrogel exhibits outstanding osteogenic potential both in vitro and in vivo. Importantly, it is the first time that a key epigenetic regulator of ten\u2010eleven translocation 2 (Tet2) is discovered to significantly elevate the continuously active the WNT\/\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010catenin through Tet2\/HDAC1\/E\u2010cadherin\/\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010catenin signaling cascade, thereby promoting PDLSCs osteogenesis. This work represents a general strategy to design the hydrogels with customized networks and biomimetic mechanics, and illustrates underlying osteogenic mechanisms that will extend the design rationales for high\u2010functional biomaterials in tissue engineering.\n                  <\/jats:p>","DOI":"10.1002\/advs.202203734","type":"journal-article","created":{"date-parts":[[2022,9,25]],"date-time":"2022-09-25T23:00:21Z","timestamp":1664146821000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Mechanically Robust Hydrogels Facilitating Bone Regeneration through Epigenetic Modulation"],"prefix":"10.1002","volume":"9","author":[{"given":"Tingting","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Orthodontics Peking University School and Hospital of Stomatology  Beijing 100081 China"},{"name":"National Center of Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; National Engineering Laboratory for Digital and Material Technology of Stomatology &amp; 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