{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T18:43:54Z","timestamp":1786128234991,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,5]]},"group-title":"Neuroscience","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000025","name":"NIMH","doi-asserted-by":"crossref","award":["MH126409"],"award-info":[{"award-number":["MH126409"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]},{"name":"MassCATS"},{"name":"The Stanley Family Foundation"},{"DOI":"10.13039\/100000957","name":"Alzheimer\u2019s Association","doi-asserted-by":"crossref","award":["ADSF-23-1054204-C"],"award-info":[{"award-number":["ADSF-23-1054204-C"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer\u2019s Association","doi-asserted-by":"crossref","award":["ADSF-25-1460070-C"],"award-info":[{"award-number":["ADSF-25-1460070-C"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Microglia play key roles in brain development, homeostasis, and neurodegeneration. Although multiple strategies for viral gene delivery to microglia have been reported, they have not been directly compared. Here, we developed microglia-targeting AAV capsids and benchmarked them against existing approaches. The novel capsids exhibit improved transduction efficiency in cultured mouse and human microglia, as well as neurons and astrocytes. However, when we compared microglial transduction efficiency of the novel capsids with published engineered and naturally occurring capsids after intracranial injection, all capsids achieved efficient and specific transduction when paired with a genome incorporating\n                  <jats:italic>IBA1<\/jats:italic>\n                  promoter and miR-124 target sites. In contrast, CAG promoter did not support efficient microglial transduction. Moreover, blood-brain barrier- crossing capsids carrying\n                  <jats:italic>IBA1<\/jats:italic>\n                  promoter and miR-124 target sites efficiently transduced microglia at high doses but exhibited off-target expression. Together, our work provides improved capsids for\n                  <jats:italic>in vitro<\/jats:italic>\n                  manipulation of microglia and establishes viral genome design, not capsid identity, as the principal determinant of efficient\n                  <jats:italic>in vivo<\/jats:italic>\n                  microglial targeting.\n                <\/jats:p>","DOI":"10.64898\/2026.08.05.739854","type":"posted-content","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T21:20:12Z","timestamp":1785964812000},"source":"Crossref","is-referenced-by-count":0,"title":["Comparative analysis of microglia-targeted AAVs reveals capsid choice drives efficiency\n                  <i>in vitro<\/i>\n                  but has limited impact\n                  <i>in vivo<\/i>"],"prefix":"10.64898","author":[{"given":"Sa\u0161a","family":"Jereb","sequence":"first","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lia R.","family":"D\u2019Alessandro","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0346-9651","authenticated-orcid":false,"given":"Nader","family":"Morshed","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Boston Children\u2019s Hospital, Kirby Neurobiology Center, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margery","family":"Chen","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafaela","family":"Sartore","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Demers","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dara","family":"Cuffe","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Rakosi-Schmidt","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luira","family":"Leite","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youtong","family":"Huang","sequence":"additional","affiliation":[{"name":"Boston Children\u2019s Hospital, Kirby Neurobiology Center, Boston, MA, 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Infectious Diseases, Boston Children\u2019s Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Arlotta","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan","family":"Sheng","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariko L.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"},{"name":"Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew 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