@article{3d909cab798446ae86ae58ac450ccea1,
title = "On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles",
abstract = "Lipid nanoparticles (LNPs) are a clinically mature technology for the delivery of genetic medicines but have limited therapeutic applications due to liver accumulation. Recently, our laboratory developed selective organ targeting (SORT) nanoparticles that expand the therapeutic applications of genetic medicines by enabling delivery of messenger RNA (mRNA) and gene editing systems to non-liver tissues. SORT nanoparticles include a supplemental SORT molecule whose chemical structure determines the LNP's tissue-specific activity. To understand how SORT nanoparticles surpass the delivery barrier of liver hepatocyte accumulation, we studied the mechanistic factors which define their organ-targeting properties. We discovered that the chemical nature of the added SORT molecule controlled biodistribution, global/apparent pKa,and serum protein interactions of SORT nanoparticles. Additionally, we provide evidence for an endogenous targeting mechanism whereby organ targeting occurs via 1) desorption of poly(ethylene glycol) lipids from the LNP surface, 2) binding of distinct proteins to the nanoparticle surface because of recognition of exposed SORT molecules, and 3) subsequent interactions between surfacebound proteins and cognate receptors highly expressed in specific tissues. These findings establish a crucial link between the molecular composition of SORT nanoparticles and their unique and precise organ-targeting properties and suggest that the recruitment of specific proteins to a nanoparticle's surface can enable drug delivery beyond the liver.",
keywords = "Endogenous targeting, Gene editing, Lipid nanoparticles, MRNA delivery",
author = "Dilliard, {Sean A.} and Qiang Cheng and Siegwart, {Daniel J.}",
note = "Funding Information: D.J.S. acknowledges grant support from the Cystic Fibrosis Foundation (SIEGWA18XX0), the NIH National Institute of Biomedical Imaging and Bioengineering (R01 EB025192-01A1), the Cancer Prevention and Research Institute of Texas (RP190251), and the American Cancer Society (RSG-17-012-01). We acknowledge the Southwestern Small Animal Imaging Shared Resource, which is supported in part by the Harold C. Simmons Cancer Center through a National Cancer Institute Cancer Center Support Grant (P30 CA142543). We acknowledge the University of Texas Southwestern Proteomics Core for its assistance with the mass spectrometry proteomics experiments. We especially thank Prof. Andrew Lemoff for insightful advice regarding mass spectrometry experiments. S.A.D. acknowledges financial support from the NIH Pharmacological Sciences Training Grant (GM007062) and the NIH Molecular Medicine Training Grant (GM109776). Cartoons for the figurewere created using Biorender.com. Funding Information: ACKNOWLEDGMENTS. D.J.S. acknowledges grant support from the Cystic Fibrosis Foundation (SIEGWA18XX0), the NIH National Institute of Biomedical Imaging and Bioengineering (R01 EB025192-01A1), the Cancer Prevention and Research Institute of Texas (RP190251), and the American Cancer Society (RSG-17-012-01). We acknowledge the Southwestern Small Animal Imaging Shared Resource, which is supported in part by the Harold C. Simmons Cancer Center through a National Cancer Institute Cancer Center Support Grant (P30 CA142543). We acknowledge the University of Texas Southwestern Proteomics Core for its assistance with the mass spectrometry proteomics experiments. We especially thank Prof. Andrew Lemoff for insightful advice regarding mass spectrometry experiments. S.A.D. acknowledges financial support from the NIH Pharmacological Sciences Training Grant (GM007062) and the NIH Molecular Medicine Training Grant (GM109776). Cartoons for the figure were created using Biorender.com. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = dec,
day = "28",
doi = "10.1073/pnas.2109256118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "52",
}