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A fatal genetic condition, characterized by the progressive loss of striatal neurons, HD is hindered by the lack of endogenous repair in the adult brain. Recent efforts toward protecting neural circuits through neurotrophic support using brain\u2010derived neurotrophic factor (BDNF) have been suboptimal due to the protein's short half\u2010life and limited diffusion. Addressing this, adeno\u2010associated viral vectors (AAV) can be employed as a delivery tool to spatially transduce cells, enabling the localised production of BDNF with consequential neuron protection and\/or plasticity, yet present their own constraints. To overcome these known challenges of AAV gene delivery, an injectable, physiologically stable hydrogel\u2010mimic of the brain's extracellular matrix was fabricated to encapsulate the AAVs. This smart system both shielded and constrained the AAV; optimising transfection and therefore elevated and sustained BDNF presentation at the target site. Here, we achieved high neuroprotection using AAVDJ\u2010BDNF delivered through a hydrogel formed via self\u2010assembling peptide nanoscaffolds. These findings support the notion that the spatiotemporal release of BDNF to striatal neurons, facilitated by engineered biomaterial delivery systems, demonstrates tremendous promise by enhancing the efficacy of gene therapy targeted at slowing neurodegenerative disease progression.<\/jats:p>","DOI":"10.1002\/smll.202510539","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T08:01:57Z","timestamp":1769673717000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Renovating Neural Networks With Viral\u2010Mediated Gene Transfer From A Tissue Contacting Matrix Mimic"],"prefix":"10.1002","volume":"22","author":[{"given":"Shiva Soltani","family":"Dehnavi","sequence":"first","affiliation":[{"name":"ANU College of Engineering Computing, and Cybernetics  Canberra Australian Capital Territory Australia"},{"name":"Genome Sciences and Cancer Division The John Curtin School of Medical Research ANU College of Health &amp; Medicine  Canberra Australian Capital Territory Australia"},{"name":"The Eccles Institute of Neuroscience The John Curtin School of Medical Research ANU College of Science &amp; Medicine  Canberra Australian Capital Territory Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Negar","family":"Mahmoudi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Faculty of Engineering and Information Technology The University of Melbourne  Melbourne Victoria Australia"},{"name":"The Graeme Clark Institute The University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Faculty of Engineering and Information Technology The University of Melbourne  Melbourne Victoria Australia"},{"name":"The Graeme Clark Institute The University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Cheeseman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Faculty of Engineering and Information Technology The University of Melbourne  Melbourne Victoria Australia"},{"name":"The Graeme Clark Institute The University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Genome Sciences and Cancer Division The John Curtin School of Medical Research ANU College of Health &amp; Medicine  Canberra Australian Capital Territory Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross D.","family":"Hannan","sequence":"additional","affiliation":[{"name":"Genome Sciences and Cancer Division The John Curtin School of Medical Research ANU College of Health &amp; Medicine  Canberra Australian Capital Territory Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leszek","family":"Lisowski","sequence":"additional","affiliation":[{"name":"Translational Vectorology Research Unit Children's Medical Research Institute Faculty of Medicine and Health The University of Sydney  Sydney New South Wales Australia"},{"name":"Vector and Genome Engineering Facility Children's Medical Research Institute Faculty of Medicine and Health The University of Sydney  Sydney New South Wales Australia"},{"name":"Australian Genome Therapeutics Centre Children's Medical Research Institute and Sydney Children's Hospitals Network  Sydney Australia"},{"name":"Military Institute of Medicine Laboratory of Molecular Oncology and Innovative Therapies  Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent S. 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