{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:54:10Z","timestamp":1791212050735,"version":"4.1.0"},"reference-count":65,"publisher":"American Association for the Advancement of Science (AAAS)","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 82572432"],"award-info":[{"award-number":["No. 82572432"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["spj.science.org"],"crossmark-restriction":true},"short-container-title":["Research"],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"<jats:p>\n                    Diabetic bone defects are difficult to repair because chronic hypoxia, oxidative stress, persistent inflammation, and impaired osteoangiogenic coupling disrupt the healing cascade. Here, we report a pH-responsive polysaccharide hydrogel, GOZ6, for spatiotemporally coordinated diabetic bone regeneration. GOZ6 is formed by dynamic Schiff base crosslinking between gelatin and oxidized konjac glucomannan and co-delivers ZIF-8@CaO\n                    <jats:sub>2<\/jats:sub>\n                    and 6-gingerol, integrating gated oxygen release, calcium ion delivery, antioxidative protection, and immunomodulation. The hydrogel exhibited rapid gelation within approximately 67 s, a porous architecture with a porosity of 75.78%, pH-responsive degradation, and sustained oxygen release for up to 14 d under physiological conditions. Under mildly acidic conditions, approximately 60% of 6-gingerol was released within the first 3 d, supporting early anti-inflammatory and antioxidative intervention. In\u00a0vitro, GOZ6 maintained cell viability above 90%, promoted macrophage polarization toward a reparative phenotype, suppressed pro-inflammatory cytokine production, and restored oxidative metabolism. Transcriptomic and protein analyses find that JAK1\u2013STAT3 and PI3K\u2013AKT may serve as central pathways involved in these effects. Moreover, the GOZ6-conditioned immune microenvironment enhanced endothelial migration and tube formation, alleviated oxidative stress in bone marrow mesenchymal stem cells, restored mitochondrial function, and promoted osteogenic differentiation. In a diabetic rat calvarial defect model, GOZ6 markedly enhanced vascularized bone regeneration, collagen deposition, and osteogenic marker expression while reducing local inflammation, without evident systemic toxicity. GOZ6 therefore provides a multifunctional strategy for converting diabetic bone defects into a repair-permissive microenvironment.\n                  <\/jats:p>","DOI":"10.34133\/research.1428","type":"journal-article","created":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T22:29:31Z","timestamp":1787524171000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":0,"title":["A pH-Responsive Polysaccharide Hydrogel Modulates Oxygen Delivery and Immunometabolic Remodeling for Diabetic Bone Regeneration"],"prefix":"10.34133","volume":"9","author":[{"given":"Haifu","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Orthopedics, \rThe First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China."},{"name":"Department of Orthopedics, Shanghai Tenth People\u2019s Hospital, School of Medicine, \rTongji University, Shanghai 200072, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanning","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Lianyungang Clinical College, \rXuzhou Medical University, Lianyungang Second People\u2019s Hospital affiliated to Kangda College of Nanjing Medical University, Lianyungang 222003, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Oncology, Shanghai General Hospital, \rShanghai Jiao Tong University School of Medicine, Shanghai 200000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Geng","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, \rThe First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shanghai Tenth People\u2019s Hospital, School of Medicine, \rTongji University, Shanghai 200072, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhui","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shanghai Tenth People\u2019s Hospital, School of Medicine, \rTongji University, Shanghai 200072, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonggang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, \rThe First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, \rThe First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haowen","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, \rThe First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, \rThe Second Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longpo","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shanghai Tenth People\u2019s Hospital, School of Medicine, \rTongji University, Shanghai 200072, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2441-6687","authenticated-orcid":true,"given":"Yusen","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, \rThe First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.r1726","article-title":"Management of type 2 diabetes","volume":"390","author":"Theodoraki A","year":"2025","unstructured":"Theodoraki A. 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Drugs. 2024;84(9):1111\u20131134.","journal-title":"Drugs"},{"issue":"10","key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/s41574-022-00707-1","article-title":"Bone fragility in type 2 diabetes mellitus: A lot left to explore","volume":"18","author":"Pal R","year":"2022","unstructured":"Pal R, Prasad TN, Bhadada SK. Bone fragility in type 2 diabetes mellitus: A lot left to explore. Nat Rev Endocrinol. 2022;18(10):651.","journal-title":"Nat Rev Endocrinol"},{"issue":"23","key":"e_1_3_4_6_2","doi-asserted-by":"crossref","DOI":"10.1002\/advs.202415667","article-title":"Targeted delivery of \u03b1-ketoglutarate to macrophages in bone: A novel therapeutic strategy for improving fracture healing in type 2 diabetes","volume":"12","author":"Wang J","year":"2025","unstructured":"Wang J, Cao J, Zhang S, Chen H, Yu X, Wang X, Wang T, Cao W, Dong W, Lin X, et al. 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