{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:08:26Z","timestamp":1785424106644,"version":"3.56.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontierspartnerships.org"],"crossmark-restriction":true},"short-container-title":["Acta Biochim. Pol."],"abstract":"<jats:p>\n                    Adeno-associated virus (AAV) vectors have become central to\n                    <jats:italic>in vivo<\/jats:italic>\n                    gene therapy across genetic and acquired diseases. Yet despite extensive preclinical validation, AAV programs often encounter translational gaps when advancing from rodents to non-human primates (NHPs) and ultimately to humans. These species barriers arise from differences in capsid\u2013receptor interactions, intracellular trafficking, immune landscapes, and tissue microanatomy. Even within species, strain-level genetic variation can markedly alter vector performance, exemplified by the LY6A-dependent central nervous system (CNS) tropism of AAV-PhP.B in C57BL\/6J mice. Old world monkeys, which are evolutionarily closer to humans than new world species, remain the most widely used models for systemic and CNS delivery, yet discrepancies in seroprevalence, complement activity, endothelial biology, and neuronal susceptibility still limit predictability. Recent advances, including machine learning\u2013guided capsid design, deep mutational scanning, and human-derived organoids and explant models, offer powerful tools to bridge these barriers. This mini-review synthesizes current understanding of AAV species barriers and outlines strategies that enhance the robustness and human relevance of AAV gene therapy development.\n                  <\/jats:p>","DOI":"10.3389\/abp.2026.15939","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T06:10:22Z","timestamp":1774505422000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Species barriers in AAV tropism: mechanisms, models, and emerging solutions for clinical translation"],"prefix":"10.3389","volume":"73","author":[{"given":"Xinyuan","family":"Xu","sequence":"first","affiliation":[{"name":"Postdoctoral Research Workstation, Beijing State-owned Capital Operation and Management Company Limited","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1354055","DOI":"10.3389\/fimmu.2024.1354055","article-title":"Essential role of pre-existing humoral immunity in TLR9-mediated type I IFN response to recombinant AAV vectors in human whole blood","volume":"15","author":"Alakhras","year":"2024","journal-title":"Front. 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