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Gene therapy can restore these activities by regulating the expression of genes in lesion cells; however, in chronic diseases, such as alcohol-induced osteonecrosis of the femoral head (ONFH), gene therapy has failed to provide long-term effects. In this study, we developed a heat-sensitive nanocomposite hydrogel system with a secondary nanostructure that can regulate gene expression and achieve long-term gene regulation in lesion cells. This nanocomposite hydrogel exists in a liquid state at 25\u2009\u00b0C and is injectable. Once injected into the body, the hydrogel can undergo solidification induced by body heat, thereby gaining the ability to be retained in the body for a prolonged time period. With the gradual degradation of the hydrogel in vivo, the internal secondary nanostructures are continuously released. These nanoparticles carry plasmids and siRNA into lesion stem cells to promote the expression of B-cell lymphoma 2 (inhibiting the apoptosis of stem cells) and inhibit the secretion of peroxisome proliferators-activated receptors \u03b3 (PPAR\u03b3, inhibiting the adipogenic differentiation of stem cells). Finally, the physiological activity of the stem cells in the ONFH area was restored and ONFH repair was promoted. In vivo experiments demonstrated that this nanocomposite hydrogel can be indwelled for a long time, thereby providing long-term treatment effects. As a result, bone reconstruction occurs in the ONFH area, thus enabling the treatment of alcohol-induced ONFH. Our nanocomposite hydrogel provides a novel treatment option for alcohol-related diseases and may serve as a useful biomaterial for other gene therapy applications.<\/jats:p>","DOI":"10.1063\/5.0130711","type":"journal-article","created":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T19:32:43Z","timestamp":1674070363000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":19,"title":["Injectable heat-sensitive nanocomposite hydrogel for regulating gene expression in the treatment of alcohol-induced osteonecrosis of the femoral head"],"prefix":"10.1063","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9499-4485","authenticated-orcid":false,"given":"Zherui","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Emergency, The First People's Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University 1 , Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8503-8654","authenticated-orcid":false,"given":"Yi","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Emergency, The First People's Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University 1 , Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9244-0454","authenticated-orcid":false,"given":"Yaping","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 2 , 197 Ruijin 2nd Road, Shanghai 200025, People's Republic of China ."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4273-8981","authenticated-orcid":false,"given":"Feng","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The First People's Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University 3 , Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"317","published-online":{"date-parts":[[2023,1,18]]},"reference":[{"issue":"4","key":"2024031523315412100_c1","doi-asserted-by":"publisher","first-page":"441","DOI":"10.4067\/S0716-97602013000400015","volume":"46","year":"2013","journal-title":"Biol. 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