Targeting DNA‐LNPs to Endothelial Cells Improves Expression Magnitude, Duration, and Specificity
Year: 2026
Type: article
Abstract: . 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.
Source: Advanced Science
Authors: Nicolas Marzolini, Taylor V. Brysgel, Ryan J. Rahman, Eno‐Obong Essien, Saw Y. Nwe, Jichuan Wu, Aparajeeta Majumder, Manthan N. Patel, Sachchidanand Tiwari, Carolann L. Espy, Fengyi Dong, Sabrina A. Santos‐De León, Anit Shah, Vladimir V. Shuvaev, Elizabeth D. Hood, Liam S. Chase, Drew Weissman, Jeremy B. Katzen, David B. Frank, Mariko L. Bennett, Oscar A. Marcos‐Contreras, Jacob W. Myerson, Vladimir R. Muzykantov, Sahily Reyes‐Esteves, Jacob S. Brenner
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,730
Awards: G1245763193, G3498178703, G5640895878, BioFoundry: A BioFoundry for Extreme & Exceptional Fungi, Archaea and Bacteria (Ex-FAB), G7214084939, Small Molecule Drug-Loaded RNA Lipid Nanoparticles for the Treatment of Intracerebral Hemorrhage, G9000012854, G9000014072, G9000014495, G9000075100, G9000149660, G9000168448, G9000187708, G9000329180, Controlling complement to unleash nanomedicine for acute critical illnesses, Institutional Career Development Core, mRNA-LNPs for ARDS
OpenAlex ID: W7124854533