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Herein, we report the first instances of extrahepatic DNA-LNP targeting. DNA-LNPs conjugated to antibodies against PECAM-1 or VCAM-1 target the endothelium of the lungs and brain\/spleen, respectively. These LNPs drive robust transgene expression in their target organs, with greater magnitude and duration than untargeted LNPs. Lung specificity of PECAM-targeted transgene expression increases over two weeks, resulting in markedly higher lung-to-liver expression ratios than our previous PECAM-targeted mRNA-LNPs. Off-target liver DNA expression declines to undetectable levels but persists in the lungs, while mRNA expression uniformly decreases due to its short half-life. We further improve this expression specificity by replacing full-length antibodies with Fab fragments. Single-cell analysis reveals a key mechanism underlying the improvements in organ-specificity: target organ expression is dominated by long-lived endothelial cells, while off-target liver delivery and expression are in non-endothelial cells with shorter half-lives. Collectively, these studies demonstrate that targeted DNA-LNPs achieve high levels of organ- and cell-type-specific transgene expression and thus provide a therapeutic platform for dozens of endothelial-centric diseases.\n                <\/jats:p>","DOI":"10.1101\/2025.07.09.663747","type":"posted-content","created":{"date-parts":[[2025,7,13]],"date-time":"2025-07-13T01:55:13Z","timestamp":1752371713000},"source":"Crossref","is-referenced-by-count":1,"title":["Targeting DNA-LNPs to Endothelial Cells Improves Expression Magnitude, Duration, and Specificity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0658-8664","authenticated-orcid":false,"given":"Nicolas","family":"Marzolini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4791-6492","authenticated-orcid":false,"given":"Taylor 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