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Here, we develop an injectable, polymer\u2010induced self\u2010reinforcing and piezoelectric hydrogel engineered from regenerated silk fibroin, tyramine\u2010modified CMC, and MXene\u2010cellulose nanofiber nanosheets through enzymatically dynamic Cross\u2010linking. This material is designed to overcome two major limitations of current injectable hydrogels: inadequate mechanical maturation and unstable bioelectrical output. The dynamic dual\u2010network structure undergoes gradual \u03b2\u2010sheet alignment and nanointerfacial ordering, which increases the compressive modulus from \u223c0.08 to \u223c0.8\u00a0MPa and elevates piezoelectric output from 3 to 60\u00a0mV over 5 days, establishing a mechanically stable and electrically active microenvironment within the defect. The hydrogel\u2010derived electrical signals induce Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx and activate the CaMKII\/CREB\/P300 axis, enhancing H3K9 acetylation and reinitiating osteogenic transcription, with PTH1R emerging as a key downstream effector. This hydrogel promotes osteogenic differentiation, mineralization, and angiogenesis in vitro and accelerates new bone formation while restoring trabecular architecture in critical\u2010sized defects in vivo. Overall, this mechanoadaptive hydrogel provides sustained piezoelectric stimulation while functioning as an epigenetic activator to reprogram the osteogenic microenvironment, offering a promising strategy for irregular bone defect repair.\n                  <\/jats:p>","DOI":"10.1002\/advs.77911","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:58:28Z","timestamp":1791352708000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Injectable and Self\u2010Reinforced Piezoelectric Hydrogel for Irregular Bone Defects Regeneration: Dynamic Epigenetic Regulation Approach"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6560-8715","authenticated-orcid":false,"given":"Yu\u2010Kai","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai People's Republic of 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of Science and Technology  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen\u2010Hui","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Zhongshan Hospital (Xiamen) Fudan University  Fujian People's Republic of China"},{"name":"Xiamen Osteoporosis Specialized Prevention and Treatment Center  Xiamen People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7678-6594","authenticated-orcid":false,"given":"Zeng\u2010Gan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Zhongshan Hospital Fudan University  Shanghai People's Republic of China"},{"name":"Department of Orthopedic Surgery Zhongshan Hospital (Xiamen) Fudan University  Fujian People's Republic of China"},{"name":"Xiamen Osteoporosis Specialized Prevention and Treatment Center  Xiamen People's Republic of 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