{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:17:55Z","timestamp":1788218275791,"version":"build-2803163510"},"reference-count":96,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["GNT 1144996"],"award-info":[{"award-number":["GNT 1144996"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Australian Research Council","doi-asserted-by":"publisher","award":["DP220102549"],"award-info":[{"award-number":["DP220102549"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Australian Research Council","doi-asserted-by":"publisher","award":["FT230100220"],"award-info":[{"award-number":["FT230100220"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Australian Microscopy and Microanalysis Research Facility","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The central nervous system exhibits limited capacity for regeneration following injury or disease. Although genetic and epigenetic reprogramming of non-neuronal cells into induced neurons offers a promising route for neuronal replacement and circuit reconstruction, its therapeutic potential remains constrained by low reprogramming efficiency and inadequate control over factor delivery. Here, we report a high-efficiency astrocyte-to-neuron reprogramming strategy enabled by ectopic expression of the transcription factor SOX2 delivered via adeno-associated viral vectors. We further engineered an implantable hybrid composite biomaterial that functions as a localized \u201creprogramming workshop\u201d, performing sequential operations within the lesion microenvironment. Upon injection, the material forms a tissue-mimetic hydrogel that recruits endogenous astrocytes, concentrates reprogramming cues, and spatially confines their presentation. This system effectively entrapped astrocytes, guided their transition through a neuroblast-like intermediate state, and yielded robust populations of mature neurons. Incorporation of sustained valproic acid release further enhanced neuronal maturation. Together, these results present a design-led strategy for minimally invasive, tissue-optimized delivery of reprogramming factors and demonstrate a multifunctional biomaterial platform that significantly enhances neural repair potential.<\/jats:p>","DOI":"10.1021\/acsnano.6c03424","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T12:01:45Z","timestamp":1786536105000},"page":"23200-23222","source":"Crossref","is-referenced-by-count":0,"title":["Spatially Precise\nNeuron Formation via Hydrogel-Mediated\nModulation of the Host Astrocyte Response"],"prefix":"10.1021","volume":"20","author":[{"given":"Negar","family":"Mahmoudi","sequence":"first","affiliation":[{"name":"Australian National University , , , ,","place":["Canberra, Australian Capital Territory, Australia, 2601"]},{"name":"The University of Melbourne , , Melbourne , , ,","place":["Parkville, Victoria, Australia, 3010"]},{"name":"The University of Melbourne , , Melbourne , , ,","place":["Parkville, Victoria, Australia, 3010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan R.","family":"Harvey","sequence":"additional","affiliation":[{"name":"The University of Western Australia , , , ,","place":["Perth, Western Australia, Australia, 6009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niamh","family":"Moriarty","sequence":"additional","affiliation":[{"name":"The University of Melbourne , , Melbourne , , ,","place":["Parkville, Victoria, Australia, 3010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-9684","authenticated-orcid":true,"given":"Morteza","family":"Mahmoudi","sequence":"additional","affiliation":[{"name":"Michigan State University , , , ,","place":["East Lansing, Michigan, United States, 48824"]},{"name":"Brigham & Women\u2019s Hospital, Harvard Medical School , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3725-2928","authenticated-orcid":true,"given":"Wei","family":"Tong","sequence":"additional","affiliation":[{"name":"The University of Melbourne , , , ,","place":["Melbourne, Victoria, Australia, 3010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toon","family":"Goris","sequence":"additional","affiliation":[{"name":"The University of Melbourne , , , ,","place":["Melbourne, Victoria, Australia, 3010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Reynolds","sequence":"additional","affiliation":[{"name":"The Australian National University , , , ,","place":["Canberra, Australian Capital Territory, Australia, 2601"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noorya Y.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"The Australian National University , , , ,","place":["Canberra, Australian Capital Territory, Australia, 2601"]},{"name":"The University of Queensland , , , ,","place":["Brisbane, Queensland, Australia, 4072"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Dehorter","sequence":"additional","affiliation":[{"name":"The Australian National University , , , ,","place":["Canberra, Australian Capital Territory, Australia, 2601"]},{"name":"The University of Queensland , , , ,","place":["Brisbane, Queensland, Australia, 4072"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leszek","family":"Lisowski","sequence":"additional","affiliation":[{"name":"The University of Sydney, Children\u2019s Medical Research Institute , , , ,","place":["Westmead, New South Wales, Australia, 2145"]},{"name":"The University of Sydney, Children\u2019s Medical Research Institute , , , ,","place":["Westmead, New South Wales, Australia, 2145"]},{"name":"Children\u2019s Medical Research Institute and Sydney Children\u2019s Hospitals Network , , , ,","place":["Westmead, New South Wales, Australia, 2145"]},{"name":"Military Institute of Medicine\u2500National Research Institute , , ,","place":["Warsaw, Poland, 04-141"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare L.","family":"Parish","sequence":"additional","affiliation":[{"name":"The University of Melbourne , , Melbourne , , ,","place":["Parkville, Victoria, Australia, 3010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3831-8738","authenticated-orcid":true,"given":"Richard J.","family":"Williams","sequence":"additional","affiliation":[{"name":"The University of Melbourne , , Melbourne , , ,","place":["Parkville, Victoria, Australia, 3010"]},{"name":"Deakin University , , , ,","place":["Geelong, Victoria, Australia, 3217"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1343-0769","authenticated-orcid":true,"given":"David R.","family":"Nisbet","sequence":"additional","affiliation":[{"name":"The University of Melbourne , , Melbourne , , ,","place":["Parkville, Victoria, Australia, 3010"]},{"name":"The University of Melbourne , , Melbourne , , ,","place":["Parkville, Victoria, Australia, 3010"]},{"name":"The University of Melbourne , , Melbourne , , ,","place":["Parkville, Victoria, Australia, 3010"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"2026083119013368300_cit1","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1017\/cjn.2024.62","article-title":"Integrated Care in Neurology: The\nCurrent Landscape and Future Directions","volume":"52","author":"Feng","year":"2024","journal-title":"Can.\nJ. Neurol. Sci."},{"issue":"590","key":"2026083119013368300_cit2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaz6747","article-title":"Patient-Derived\nGlial Enriched Progenitors Repair Functional Deficits Due to White\nMatter Stroke and Vascular Dementia in Rodents","volume":"13","author":"Llorente","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"2026083119013368300_cit3","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1038\/s41593-020-00783-4","article-title":"Reactive Astrocyte\nNomenclature, Definitions, and Future Directions","volume":"24","author":"Escartin","year":"2021","journal-title":"Nat. Neurosci."},{"issue":"10","key":"2026083119013368300_cit4","doi-asserted-by":"publisher","first-page":"2761","DOI":"10.1093\/brain\/awl165","article-title":"Essential\nProtective Roles of Reactive Astrocytes in Traumatic Brain Injury","volume":"129","author":"Myer","year":"2006","journal-title":"Brain"},{"issue":"6","key":"2026083119013368300_cit5","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1002\/glia.21156","article-title":"Progenitors in the Adult Cerebral\nCortex: Cell Cycle Properties and Regulation by Physiological Stimuli\nand Injury","volume":"59","author":"Simon","year":"2011","journal-title":"Glia"},{"issue":"2","key":"2026083119013368300_cit6","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1038\/nrn1326","article-title":"Regeneration beyond the Glial Scar","volume":"5","author":"Silver","year":"2004","journal-title":"Nat. Rev. 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Ther."},{"issue":"4","key":"2026083119013368300_cit11","doi-asserted-by":"publisher","first-page":"3597","DOI":"10.1021\/acsnano.3c11337","article-title":"Neuronal Replenishment\nvia Hydrogel-Rationed Delivery\nof Reprogramming Factors","volume":"18","author":"Mahmoudi","year":"2024","journal-title":"ACS Nano"},{"issue":"11","key":"2026083119013368300_cit12","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1038\/nn1131","article-title":"Vertebrate Neurogenesis\nIs Counteracted by Sox1\u20133 Activity","volume":"6","author":"Bylund","year":"2003","journal-title":"Nat.\nNeurosci."},{"issue":"5","key":"2026083119013368300_cit13","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.tins.2005.03.002","article-title":"A Multi-Photon\nWindow onto Neuronal-Glial-Vascular Communication","volume":"28","author":"Hirase","year":"2005","journal-title":"Trends Neurosci."},{"issue":"15","key":"2026083119013368300_cit14","doi-asserted-by":"publisher","first-page":"3805","DOI":"10.1242\/dev.01204","article-title":"Sox2 Deficiency\nCauses Neurodegeneration and Impaired Neurogenesis in the Adult Mouse\nBrain","volume":"131","author":"Ferri","year":"2004","journal-title":"Development"},{"issue":"6","key":"2026083119013368300_cit15","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1016\/j.cell.2012.02.031","article-title":"Reprogramming Cellular Identity for Regenerative Medicine","volume":"148","author":"Cherry","year":"2012","journal-title":"Cell"},{"issue":"March","key":"2026083119013368300_cit16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fnagi.2021.612856","article-title":"Conversion\nof Reactive Astrocytes to Induced Neurons Enhances Neuronal Repair\nand Functional Recovery After Ischemic Stroke","volume":"13","author":"Jiang","year":"2021","journal-title":"Front. Aging Neurosci."},{"issue":"2","key":"2026083119013368300_cit17","doi-asserted-by":"publisher","first-page":"342","DOI":"10.4103\/1673-5374.265185","article-title":"Differential\nNeuronal Reprogramming Induced by NeuroD1 from Astrocytes in Grey\nMatter versus White Matter","volume":"15","author":"Liu","year":"2020","journal-title":"Neural Regener.\nRes."},{"issue":"1","key":"2026083119013368300_cit18","doi-asserted-by":"publisher","first-page":"22490","DOI":"10.1038\/srep22490","article-title":"In Vivo Reprogramming\nReactive Glia into IPSCs to Produce New Neurons in the Cortex Following\nTraumatic Brain Injury","volume":"6","author":"Gao","year":"2016","journal-title":"Sci. Rep."},{"issue":"10","key":"2026083119013368300_cit19","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1038\/ncb2843","article-title":"In Vivo Reprogramming of Astrocytes\nto Neuroblasts in the Adult Brain","volume":"15","author":"Niu","year":"2013","journal-title":"Nat. Cell\nBiol."},{"issue":"4","key":"2026083119013368300_cit20","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1016\/j.cell.2006.07.024","article-title":"Induction\nof Pluripotent Stem Cells from Mouse Embryonic\nand Adult Fibroblast Cultures by Defined Factors","volume":"126","author":"Takahashi","year":"2006","journal-title":"Cell"},{"issue":"5","key":"2026083119013368300_cit21","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction\nof Pluripotent Stem Cells\nfrom Adult Human Fibroblasts by Defined Factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"issue":"12","key":"2026083119013368300_cit22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015526","article-title":"High-Efficient\nGeneration of Induced\nPluripotent Stem Cells from Human Astrocytes","volume":"5","author":"Ruiz","year":"2010","journal-title":"PLoS One"},{"issue":"7471","key":"2026083119013368300_cit23","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1038\/nature12586","article-title":"Reprogramming in Vivo\nProduces Teratomas and IPS Cells with Totipotency Features","volume":"502","author":"Abad","year":"2013","journal-title":"Nature"},{"issue":"4","key":"2026083119013368300_cit24","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1016\/j.cell.2014.01.005","article-title":"Premature Termination of Reprogramming\nin Vivo Leads to Cancer Development through Altered Epigenetic Regulation","volume":"156","author":"Ohnishi","year":"2014","journal-title":"Cell"},{"issue":"5","key":"2026083119013368300_cit25","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1016\/j.stem.2021.02.009","article-title":"In Vivo\nReprogramming of NG2 Glia Enables Adult Neurogenesis and Functional\nRecovery Following Spinal Cord Injury","volume":"28","author":"Tai","year":"2021","journal-title":"Cell\nStem Cell"},{"issue":"4","key":"2026083119013368300_cit26","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1002\/jcb.22775","article-title":"Teratomas from Pluripotent Stem Cells:\nA Clinical Hurdle","volume":"111","author":"Fong","year":"2010","journal-title":"J. Cell. Biochem."},{"issue":"1","key":"2026083119013368300_cit27","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.cell.2009.03.034","article-title":"A Fresh Look\nat IPS Cells","volume":"137","author":"Yamanaka","year":"2009","journal-title":"Cell"},{"issue":"7","key":"2026083119013368300_cit28","doi-asserted-by":"publisher","first-page":"1414","DOI":"10.3390\/ijms18071414","article-title":"Histone Deacetylase\nInhibitors as Anticancer Drugs","volume":"18","author":"Eckschlager","year":"2017","journal-title":"Int. J. Mol.\nSci."},{"issue":"6789","key":"2026083119013368300_cit29","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1038\/35016083","article-title":"Induction\nof Neurogenesis in the\nNeocertex of Adult Mice","volume":"405","author":"Magavi","year":"2000","journal-title":"Nature"},{"issue":"1","key":"2026083119013368300_cit30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40824-016-0086-y","article-title":"Direct Reprogramming\nand Biomaterials for Controlling Cell Fate","volume":"20","author":"Kim","year":"2016","journal-title":"Biomater. Res."},{"key":"2026083119013368300_cit31","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.coche.2017.01.001","article-title":"Biophysical Regulation of Cell Reprogramming","volume":"15","author":"Wong","year":"2017","journal-title":"Curr. Opin. Chem. 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Rep."},{"issue":"1","key":"2026083119013368300_cit41","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/s41427-021-00304-0","article-title":"Matrix Stiffness\nChanges Affect Astrocyte Phenotype in an in Vitro Injury Model","volume":"13","author":"Hu","year":"2021","journal-title":"NPG Asia Mater."},{"issue":"3","key":"2026083119013368300_cit42","doi-asserted-by":"publisher","first-page":"624671","DOI":"10.1007\/s10409-024-24671-x","article-title":"Viscoelastic Microenvironment\nas Key Regulators of Astrocyte Behavior in Brain Injury and Scar Formation","volume":"42","author":"Hu","year":"2026","journal-title":"Acta Mech. Sin."},{"issue":"9","key":"2026083119013368300_cit43","doi-asserted-by":"publisher","first-page":"9084","DOI":"10.1021\/acsnano.7b03732","article-title":"Development of a\nVirtual Cell Model to Predict Cell Response to Substrate Topography","volume":"11","author":"Heydari","year":"2017","journal-title":"ACS Nano"},{"issue":"13","key":"2026083119013368300_cit44","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.1039\/C6TB03130G","article-title":"A Biomaterial Approach\nto Cell Reprogramming and Differentiation","volume":"5","author":"Long","year":"2017","journal-title":"J.\nMater. Chem. B"},{"issue":"8","key":"2026083119013368300_cit45","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1038\/s41428-020-0351-8","article-title":"The Correlations\nbetween Structure, Rheology, and Cell Growth in Peptide-Based Multicomponent\nHydrogels","volume":"52","author":"Du","year":"2020","journal-title":"Polym. J."},{"key":"2026083119013368300_cit46","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202510539","article-title":"Renovating\nNeural Networks With Viral-Mediated Gene Transfer From A Tissue Contacting\nMatrix Mimic","volume":"22","author":"Dehnavi","year":"2026","journal-title":"Small"},{"issue":"June","key":"2026083119013368300_cit47","doi-asserted-by":"publisher","first-page":"146857","DOI":"10.1016\/j.cej.2023.146857","article-title":"Molecular\nCamouflage by a Context-Specific Hydrogel as the Key to Unlock the\nPotential of Viral Vector Gene Therapy","volume":"477","author":"Soltani Dehnavi","year":"2023","journal-title":"Chem.\nEng. J."},{"issue":"5","key":"2026083119013368300_cit48","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1038\/s41434-019-0075-6","article-title":"Astrocyte-Selective\nAAV Gene Therapy\nthrough the Endogenous GFAP Promoter Results in Robust Transduction\nin the Rat Spinal Cord Following Injury","volume":"26","author":"Griffin","year":"2019","journal-title":"Gene\nTher."},{"issue":"1","key":"2026083119013368300_cit49","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/mt.2014.180","article-title":"Widespread and Efficient Transduction of Spinal Cord\nand Brain Following Neonatal AAV Injection and Potential Disease Modifying\nEffect in ALS Mice","volume":"23","author":"Ayers","year":"2015","journal-title":"Mol. 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