{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T17:25:03Z","timestamp":1787073903794,"version":"build-2736575974"},"reference-count":41,"publisher":"American Chemical Society (ACS)","issue":"32","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No.32571692"],"award-info":[{"award-number":["No.32571692"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No.82302711"],"award-info":[{"award-number":["No.82302711"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011501","name":"Qinghai Provincial Department of Science and Technology","doi-asserted-by":"publisher","award":["2026-ZJ-Z33"],"award-info":[{"award-number":["2026-ZJ-Z33"]}],"id":[{"id":"10.13039\/501100011501","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Changsha Natural Science Foundation Project","award":["No.Kq2403141"],"award-info":[{"award-number":["No.Kq2403141"]}]},{"name":"China Postdoctoral Science Foundation Funded Project","award":["No. 2023M743956"],"award-info":[{"award-number":["No. 2023M743956"]}]},{"name":"Hunan Natural Science Foundation Project","award":["No. 2023JJ40864"],"award-info":[{"award-number":["No. 2023JJ40864"]}]},{"name":"Hunan Natural Science Foundation Project","award":["No. 2025JJ50610"],"award-info":[{"award-number":["No. 2025JJ50610"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Pyrolusite, a traditional mineral medicine rich in manganese, has long been used to promote fracture healing; however, its complex composition, limited bioavailability, and poorly defined mechanisms have hindered its modernization and clinical translation. Here, we present a nanotechnology-enabled strategy to modernize pyrolusite by constructing a pyrolusite-derived MnO2 nanoplatform for osteo-angio-immunomodulatory bone repair. Pyrolusite nanosuspensions were prepared via a top-down high-energy ball-milling approach and incorporated into an injectable chitosan\/\u03b2-glycerophosphate thermosensitive hydrogel, thereby enabling precise local delivery and sustained release. By directly comparing natural pyrolusite with its monomeric component MnO2, we elucidated the pharmacological substance basis of pyrolusite-mediated bone repair. Comprehensive in vitro and in vivo studies demonstrated that both materials promote osteogenic differentiation, suppress osteoclastogenesis, enhance angiogenesis, and induce reparative M2 macrophage polarization, thereby reshaping the bone-regeneration microenvironment. Transcriptomic analysis combined with protein\u2013protein interaction mapping and phosphorylation validation identified the PI3K\u2013Akt signaling pathway as a central regulatory hub orchestrating these effects, with MnO2 exhibiting consistently stronger biological activity and pathway activation than natural pyrolusite. In a mouse femoral defect model, MnO2-loaded hydrogels significantly accelerated bone regeneration, improved bone microarchitecture and vascularization, modulated immune responses, and exhibited excellent in vivo biosafety. Collectively, this work establishes a translatable paradigm for upgrading traditional mineral medicine into a mechanism-driven nanotherapeutic platform and highlights the potential of mineral-derived nanomedicine for high-quality bone regeneration.<\/jats:p>","DOI":"10.1021\/acsnano.6c01387","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T19:01:56Z","timestamp":1785870116000},"page":"22452-22474","source":"Crossref","is-referenced-by-count":0,"title":["Modernizing\nTraditional Mineral Medicine: Pyrolusite-Derived\nMnO2 Nanoplatform for Osteo-Angio-Immunomodulatory Bone\nRepair"],"prefix":"10.1021","volume":"20","author":[{"given":"Qin","family":"Ouyang","sequence":"first","affiliation":[{"name":"The First-Affiliated Hospital of Hunan Normal University , , , ,","place":["Changsha, Hunan, China, 410005"]},{"name":"Xiangya School of Pharmaceutical Sciences, Central South University , , ,","place":["Changsha, Hunan, China, 410013"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqi","family":"Xiang","sequence":"additional","affiliation":[{"name":"The Second Xiangya Hospital of Central South University , , , ,","place":["Changsha, Hunan, China, 410011"]},{"name":"The Second Xiangya Hospital of Central South University , , , ,","place":["Changsha, Hunan, China, 410011"]},{"name":"The Second Xiangya Hospital of Central South University , , , ,","place":["Changsha, Hunan, China, 410011"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yupeng","family":"Guo","sequence":"additional","affiliation":[{"name":"The First-Affiliated Hospital of Hunan Normal University , , , ,","place":["Changsha, Hunan, China, 410005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yuan","sequence":"additional","affiliation":[{"name":"The First-Affiliated Hospital of Hunan Normal University , , , ,","place":["Changsha, Hunan, China, 410005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Chen","sequence":"additional","affiliation":[{"name":"The Second Xiangya Hospital of Central South University , , , ,","place":["Changsha, Hunan, China, 410011"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qishun","family":"Tang","sequence":"additional","affiliation":[{"name":"The First-Affiliated Hospital of Hunan Normal University , , , ,","place":["Changsha, Hunan, China, 410005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8314-547X","authenticated-orcid":true,"given":"Chunhui","family":"Hu","sequence":"additional","affiliation":[{"name":"Qinghai University , , , ,","place":["Xining, Qinghai, China, 810016"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3794-661X","authenticated-orcid":true,"given":"Wenhu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Xiangya School of Pharmaceutical Sciences, Central South University , , ,","place":["Changsha, Hunan, China, 410013"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Huang","sequence":"additional","affiliation":[{"name":"The First-Affiliated Hospital of Hunan Normal University , , , ,","place":["Changsha, Hunan, China, 410005"]},{"name":"Hunan Province Sports Medicine Clinical Medicine Research center , , ,","place":["Changsha, Hunan, China, 410013"]},{"name":"Hunan Provincial Engineering Research Center for Precision Diagnosis and Treatment and Rehabilitation of Joint and Sports Medicine Synergy of Traditional Chinese Medicine and Western Medicine , , ,","place":["Changsha, Hunan, China, 410000"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"2026081810310760700_cit1","doi-asserted-by":"publisher","first-page":"216","DOI":"10.4248\/BR201303002","article-title":"Bone Regeneration\nBased on Tissue Engineering Conceptions - 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Materials in medicine."},{"key":"2026081810310760700_cit9","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.bioactmat.2017.05.007","article-title":"Bone grafts and\nbiomaterials substitutes for bone defect\nrepair: A review","volume":"2","author":"Wang","year":"2017","journal-title":"Bioactive Materials."},{"key":"2026081810310760700_cit10","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/nrrheum.2014.164","article-title":"Fracture\nhealing: mechanisms and interventions","volume":"11","author":"Einhorn","year":"2015","journal-title":"Nature\nreviews. Rheumatology."},{"key":"2026081810310760700_cit11","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/s41584-022-00887-0","article-title":"The decisive early phase of bone\nregeneration","volume":"19","author":"Duda","year":"2023","journal-title":"Nature reviews. Rheumatology."},{"key":"2026081810310760700_cit12","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s41413-021-00138-0","article-title":"Skeleton-vasculature\nchain reaction:\na novel insight into the mystery of homeostasis","volume":"9","author":"Chen","year":"2021","journal-title":"Bone research."},{"key":"2026081810310760700_cit13","doi-asserted-by":"publisher","first-page":"4575","DOI":"10.1038\/s41467-024-48579-5","article-title":"Angiogenesis\nis\nuncoupled from osteogenesis during calvarial bone regeneration","volume":"15","author":"Bixel","year":"2024","journal-title":"Nat. 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Mater."},{"key":"2026081810310760700_cit28","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202423654","article-title":"Antimicrobial Phenolic\nMaterials: From Assembly to Function","volume":"64","author":"Xu","year":"2025","journal-title":"Angewandte\nChemie International Edition."},{"key":"2026081810310760700_cit29","doi-asserted-by":"publisher","first-page":"2417810","DOI":"10.1002\/adfm.202417810","article-title":"Nature Herbal Medicine-\nTissue Engineering Strategies for Regulate Cell Homeostasis in Bone\nRegeneration","volume":"35","author":"Wei","year":"2025","journal-title":"Advanced Functional Materials."},{"key":"2026081810310760700_cit30","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.bioactmat.2025.06.001","article-title":"One-step strategy\nfor fabricating icariin-encapsulated biomimetic Scaffold: Orchestrating\nimmune, angiogenic, and osteogenic cascade for enhanced bone regeneration","volume":"52","author":"Zhao","year":"2025","journal-title":"Bioactive Materials."},{"key":"2026081810310760700_cit31","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.2147\/DDDT.S447496","article-title":"Advances in Nanotechnology\nfor Enhancing the Solubility and Bioavailability\nof Poorly Soluble Drugs","volume":"18","author":"Liu","year":"2024","journal-title":"Drug design, development\nand therapy."},{"key":"2026081810310760700_cit32","doi-asserted-by":"publisher","first-page":"116083","DOI":"10.1016\/j.biopha.2023.116083","article-title":"From nature to nanotechnology: The\ninterplay of traditional medicine, green chemistry, and biogenic metallic\nphytonanoparticles in modern healthcare innovation and sustainability","volume":"170","author":"Puri","year":"2024","journal-title":"Biomedicine & Pharmacotherapy."},{"key":"2026081810310760700_cit33","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202411536","article-title":"High-Energy Ball Milling Enables\nan Ultra-Fast Wittig\nOlefination Under Ambient and Solvent-free Conditions","volume":"63","author":"Templ","year":"2024","journal-title":"Angewandte Chemie International Edition."},{"key":"2026081810310760700_cit34","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/s43586-025-00401-2","article-title":"Ball milling\nfor mechanochemical reactions","volume":"5","author":"Speight","year":"2025","journal-title":"Nature Reviews\nMethods Primers."},{"key":"2026081810310760700_cit35","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1186\/s12951-024-02726-8","article-title":"Repolarizing neutrophils via MnO(2)\nnanoparticle-activated STING pathway enhances Salmonella-mediated\ntumor immunotherapy","volume":"22","author":"Lu","year":"2024","journal-title":"J. Nanobiotechnology."},{"key":"2026081810310760700_cit36","doi-asserted-by":"publisher","first-page":"772","DOI":"10.3390\/polym17060772","article-title":"Recent Advances\nin\nSilk Fibroin-Based Composites for Bone Repair Applications: A Review","volume":"17","author":"Zhu","year":"2025","journal-title":"Polymers"},{"key":"2026081810310760700_cit37","doi-asserted-by":"publisher","first-page":"4264","DOI":"10.1038\/s41467-025-59651-z","article-title":"Immunomodulatory multifunctional\njanus collagen-based membrane for advanced bone regeneration","volume":"16","author":"Yang","year":"2025","journal-title":"Nature Communications."},{"key":"2026081810310760700_cit38","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202501437","article-title":"Microsphere\nStrategy to Generate Conformal Bone Organoid Units with Osteoimmunomodulation\nand Sustainable Oxygen Supply for Bone Regeneration","volume":"12","author":"Deng","year":"2025","journal-title":"Advanced Science."},{"key":"2026081810310760700_cit39","doi-asserted-by":"publisher","first-page":"154879","DOI":"10.1016\/j.cej.2024.154879","article-title":"Hypoxia regulates BG\/BMSCs@GelMA bioactive scaffolds\nto promote angiogenesis, osteogenesis and regulate immune responses\nfor bone regeneration","volume":"498","author":"Ai","year":"2024","journal-title":"Chemical Engineering\nJournal."},{"key":"2026081810310760700_cit40","doi-asserted-by":"publisher","first-page":"123352","DOI":"10.1016\/j.biomaterials.2025.123352","article-title":"Vascular endothelial\ngrowth factor (VEGF) and endogenous calcium-capturing gelatin methacrylate\nhydrogels promote bone tissue regeneration","volume":"322","author":"Yuan","year":"2025","journal-title":"Biomaterials."},{"key":"2026081810310760700_cit41","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/s41536-023-00288-1","article-title":"VEGF dose\ncontrols the coupling of angiogenesis and osteogenesis in engineered\nbone","volume":"8","author":"Grosso","year":"2023","journal-title":"npj Regenerative Medicine."}],"container-title":["ACS Nano"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsnano.6c01387","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/ancac3\/article-pdf\/20\/32\/22452\/66392403\/acsnano.6c01387.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/ancac3\/article-pdf\/20\/32\/22452\/66392403\/acsnano.6c01387.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T16:30:03Z","timestamp":1787070603000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/ancac3\/article\/20\/32\/22452\/5243580\/Modernizing-Traditional-Mineral-Medicine"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":41,"journal-issue":{"issue":"32","published-online":{"date-parts":[[2026,8,4]]},"published-print":{"date-parts":[[2026,8,18]]}},"URL":"https:\/\/doi.org\/10.1021\/acsnano.6c01387","relation":{},"ISSN":["1936-0851","1936-086X"],"issn-type":[{"value":"1936-0851","type":"print"},{"value":"1936-086X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]}}}