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Here we report an injectable metal\u2010drug supramolecular condensate formed from hafnium ions and alendronate (Hf\u2010ALN) and loaded with the COX\u20102 inhibitor celecoxib (CXB) for synergistic radioimmunotherapy of postoperative osteosarcoma. The condensate forms through coordination\u2010driven liquid\u2010liquid phase separation between Hf\n                    <jats:sup>4+<\/jats:sup>\n                    ions and alendronate, enabling local retention within postoperative bone defects and sustained therapeutic release. Upon X\u2010ray irradiation, the Hf component amplifies radiation energy deposition and reactive oxygen species generation, thereby enhancing radiation\u2010induced DNA damage and immunogenic cell death. Meanwhile, the acidic tumor microenvironment triggers responsive release of CXB and ALN; CXB inhibits the COX\u20102\/PGE\n                    <jats:sub>2<\/jats:sub>\n                    immunosuppressive pathway, while ALN promotes macrophage repolarization toward the M1 phenotype, collectively remodeling the tumor immune microenvironment. This strategy enhances dendritic cell maturation, activates cytotoxic CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, and reduces regulatory T\u2010cell infiltration. In orthotopic osteosarcoma models, CXB@Hf\u2010ALN combined with RT suppresses tumor recurrence, preserves bone integrity, inhibits pulmonary metastasis, and prolongs survival with minimal systemic toxicity, offering a promising strategy to improve postsurgical RT outcomes in osteosarcoma.\n                  <\/jats:p>","DOI":"10.1002\/advs.77569","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T04:23:03Z","timestamp":1788236583000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Injectable Metal\u2010Drug Supramolecular Condensate Enables Radiosensitization and Systemic Antitumor Immunity for Post\u2010Surgical Osteosarcoma Therapy"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4197-2039","authenticated-orcid":false,"given":"Tianhua","family":"Xiao","sequence":"first","affiliation":[{"name":"School of Chemical Engineering and Light Industry Guangdong University of Technology  Guangzhou China"},{"name":"Department of Orthopaedic Surgery Guangzhou Key Laboratory of Spine Disease Prevention and Treatment The Third Affiliated Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zunlei","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Guangzhou Key Laboratory of Spine Disease Prevention and Treatment The Third Affiliated Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuke","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Guangzhou Key Laboratory of Spine Disease Prevention and Treatment The Third Affiliated Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4573-5484","authenticated-orcid":false,"given":"Hui","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Guangzhou Key Laboratory of Spine Disease Prevention and Treatment The Third Affiliated Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Guangzhou Key Laboratory of Spine Disease Prevention and Treatment The Third Affiliated Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3237-7724","authenticated-orcid":false,"given":"Can","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery Center for Orthopedic Surgery The Third Affiliated Hospital of Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9581-4127","authenticated-orcid":false,"given":"Hongkai","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering and Light Industry Guangdong University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering and Light Industry Guangdong University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyuan","family":"Guan","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering and Light Industry Guangdong University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Guangzhou Key Laboratory of Spine Disease Prevention and Treatment The Third Affiliated Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyun","family":"Ning","sequence":"additional","affiliation":[{"name":"School of Materials Science and Engineering National Engineering Research Center for Tissue Restoration and Reconstruction South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7334-753X","authenticated-orcid":false,"given":"Guoxin","family":"Tan","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering and Light Industry Guangdong University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8056-9464","authenticated-orcid":false,"given":"Lei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Guangzhou Key Laboratory of Spine Disease Prevention and Treatment The Third Affiliated Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"issue":"1","key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1186\/s12943-024-02105-9","article-title":"Advances on Immunotherapy for Osteosarcoma","volume":"23","author":"Yu S.","year":"2024","journal-title":"Molecular Cancer"},{"issue":"4","key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.hoc.2025.04.005","article-title":"Osteosarcoma","volume":"39","author":"Bishop M. 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B.","year":"2025","journal-title":"Cancer Research"},{"issue":"1","key":"e_1_2_9_6_1","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1186\/s12885-023-11232-3","article-title":"Radiotherapy in Bone Sarcoma: The Quest for Better Treatment Option","volume":"23","author":"Locquet M.","year":"2023","journal-title":"BMC Cancer"},{"key":"e_1_2_9_7_1","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.pbiomolbio.2025.07.001","article-title":"Advances and Challenges in the Treatment of Osteosarcoma","volume":"197","author":"Wang X.","year":"2025","journal-title":"Progress in Biophysics and Molecular Biology"},{"issue":"4","key":"e_1_2_9_8_1","doi-asserted-by":"crossref","first-page":"5586","DOI":"10.1021\/acsami.1c21729","article-title":"Mineral Nanomedicine to Enhance the Efficacy of Adjuvant Radiotherapy for Treating Osteosarcoma","volume":"14","author":"Wang Y.\u2010C.","year":"2022","journal-title":"ACS Applied Materials & Interfaces"},{"key":"e_1_2_9_9_1","doi-asserted-by":"crossref","first-page":"587","DOI":"10.3389\/fendo.2019.00587","article-title":"Therapeutic Irradiation: Consequences for Bone and Bone Marrow Adipose Tissue","volume":"10","author":"Costa S.","year":"2019","journal-title":"Frontiers in Endocrinology"},{"key":"e_1_2_9_10_1","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1038\/s41586-025-08994-0","article-title":"Radiation\u2010Induced Amphiregulin Drives Tumour Metastasis","volume":"643","author":"Piffk\u00f3 A.","year":"2025","journal-title":"Nature"},{"key":"e_1_2_9_11_1","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1021\/acsnano.2c11691","article-title":"Boosting Checkpoint Immunotherapy With Biomaterials","volume":"17","author":"Liu L.","year":"2023","journal-title":"ACS Nano"},{"issue":"9","key":"e_1_2_9_12_1","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1038\/s41587-024-02448-0","article-title":"Gold\u2010siRNA Supraclusters Enhance the Anti\u2010Tumor Immune Response of Stereotactic Ablative Radiotherapy at Primary and Metastatic Tumors","volume":"43","author":"Jiang Y.","year":"2025","journal-title":"Nature Biotechnology"},{"issue":"21","key":"e_1_2_9_13_1","doi-asserted-by":"crossref","DOI":"10.1002\/adma.202206370","article-title":"Nanoparticle\u2010Mediated Radiotherapy Remodels the Tumor Microenvironment to Enhance Antitumor Efficacy","volume":"35","author":"Zhen W.","year":"2023","journal-title":"Advanced Materials"},{"key":"e_1_2_9_14_1","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.canlet.2020.11.021","article-title":"Fucoidan\u2010Coated Nanoparticles Target Radiation\u2010Induced P\u2010Selectin to Enhance Chemoradiotherapy in Murine Colorectal Cancer","volume":"500","author":"DuRoss A. N.","year":"2021","journal-title":"Cancer Letters"},{"issue":"2","key":"e_1_2_9_15_1","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1021\/acsnano.3c08917","article-title":"Synthesis and Bioapplication of Emerging Nanomaterials of Hafnium","volume":"18","author":"Skrodzki D.","year":"2024","journal-title":"ACS Nano"},{"key":"e_1_2_9_16_1","doi-asserted-by":"crossref","DOI":"10.1002\/smll.202300341","article-title":"Harnessing Hafnium\u2010Based Nanomaterials for Cancer Diagnosis and Therapy","volume":"19","author":"Ding S.","year":"2023","journal-title":"Small"},{"issue":"1","key":"e_1_2_9_17_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41413-023-00246-z","article-title":"Managing the Immune Microenvironment of Osteosarcoma: The Outlook for Osteosarcoma Treatment","volume":"11","author":"Tian H.","year":"2023","journal-title":"Bone Research"},{"issue":"6","key":"e_1_2_9_18_1","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/s41577-019-0127-6","article-title":"Macrophages as Regulators of Tumour Immunity and Immunotherapy","volume":"19","author":"DeNardo D. G.","year":"2019","journal-title":"Nature Reviews Immunology"},{"key":"e_1_2_9_19_1","doi-asserted-by":"crossref","DOI":"10.1002\/advs.202409870","article-title":"Osteosarcoma Cell\u2010Derived Migrasomes Promote Macrophage M2 Polarization to Aggravate Osteosarcoma Proliferation and Metastasis","volume":"12","author":"Liu W.","year":"2025","journal-title":"Advanced Science"},{"issue":"15","key":"e_1_2_9_20_1","doi-asserted-by":"crossref","first-page":"5207","DOI":"10.3390\/ijms21155207","article-title":"Tumor\u2010Associated Macrophages in Osteosarcoma: From Mechanisms to Therapy","volume":"21","author":"Cersosimo F.","year":"2020","journal-title":"International Journal of Molecular Sciences"},{"key":"e_1_2_9_21_1","first-page":"440","article-title":"Tumor\u2010Associated Macrophages Promote Lung Metastasis and Induce Epithelial\u2010Mesenchymal Transition in Osteosarcoma by Activating the COX\u20102\/STAT3 Axis","volume":"116","author":"Han Y.","year":"2019","journal-title":"Cancer Letters"},{"issue":"2","key":"e_1_2_9_22_1","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/s43018-025-00909-2","article-title":"Linking Macrophage Metabolism to Function in the Tumor Microenvironment","volume":"6","author":"Jin R.","year":"2025","journal-title":"Nature Cancer"},{"issue":"26","key":"e_1_2_9_23_1","article-title":"The p23 Co\u2010Chaperone is a Succinate\u2010Activated COX\u20102 Transcription Factor in Lung Adenocarcinoma Tumorigenesis","volume":"9","author":"Yu Z.","year":"2023","journal-title":"Science Advances"},{"issue":"9","key":"e_1_2_9_24_1","doi-asserted-by":"crossref","first-page":"3594","DOI":"10.1172\/JCI127755","article-title":"Tumor Cell\u2013Intrinsic EPHA2 Suppresses Antitumor Immunity by Regulating PTGS2 (COX\u20102)","volume":"129","author":"Markosyan N.","year":"2019","journal-title":"Journal of Clinical Investigation"},{"issue":"1","key":"e_1_2_9_25_1","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.ccell.2025.11.001","article-title":"Tumor\u2010Initiating Stem Cells Fine\u2010Tune the Plasticity of Neutrophils to Sculpt a Protective Niche","volume":"44","author":"Guo W.","year":"2026","journal-title":"Cancer Cell"},{"issue":"8011","key":"e_1_2_9_26_1","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41586-024-07352-w","article-title":"PGE2 Inhibits TIL Expansion by Disrupting IL\u20102 Signalling and Mitochondrial\u00a0Function","volume":"629","author":"Morotti M.","year":"2024","journal-title":"Nature"},{"issue":"8011","key":"e_1_2_9_27_1","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/s41586-024-07254-x","article-title":"PGE2 Limits Effector Expansion of Tumour\u2010Infiltrating Stem\u2010Like CD8+ T Cells","volume":"629","author":"Lacher S. 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