Branched‐Tail Lipid Nanoparticles for Intravenous mRNA Delivery to Lung Immune, Endothelial, and Alveolar Cells in Mice
Year: 2024
Type: article
Abstract: Lipid nanoparticles (LNPs) are proven safe and effective delivery systems on a global scale. However, their efficacy has been limited primarily to liver and immune cell targets. To extend the applicability of mRNA drugs, 580 ionizable lipidoids are synthesized and tested for delivery to extrahepatocellular targets. Of these, over 40 enabled protein expression in mice, with the majority transfecting the liver. Beyond the liver, several LNPs containing new, branched-tail ionizable lipidoids potently delivered mRNA to the lungs, with cell-level specificity depending on helper lipid chemistry. Incorporation of the neutral helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) at 16 mol% enabled highly specific delivery to natural killer and dendritic cells within the lung. Although inclusion of the cationic lipid 1,2-di-(9Z-octadecenoyl)-3-trimethylammonium-propane (DOTAP) improved lung tropism, it decreased cell specificity, resulting in equal transfection of endothelial and lymphoid cells. DOTAP formulations are also less favorable than DOPE formulations because they elevated liver enzyme and cytokine levels. Together, these data identify a new branched-tailed LNP with a unique ability to selectively transfect lung immune cell populations without the use of toxicity-prone cationic helper lipids. This novel vehicle may unlock RNA therapies for lung diseases associated with immune cell dysregulation, including cancer, viral infections, and autoimmune disorders.
Source: Advanced Healthcare Materials
Institution: Carnegie Mellon University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,650
Funders: National Science Foundation, Carnegie Mellon University, National Natural Science Foundation of China, National Institutes of Health, Defense Advanced Research Projects Agency, Advanced Research Projects Agency, Division of Chemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1430448282, G2515541506, Graduate Research Fellowship Program (GRFP), MRI: Acquisition of a New 500 MHz NMR Console and Accessories to Support Research and Education at Carnegie Mellon University, G3370667275, G4409596582, G5178350307, G6272279041, Purchase of a 400 MHz NMR Spectrometer, MRI: Acquisition of a New Nuclear Magnetic Resonance (NMR) Instrument with Cryoprobe at Carnegie-Mellon University, G7455981992, G7652223712, G7841801996, G8149128787, G8421555508, Fate, Function and Genetic Engineering of Breast Milk Cells for Infant Therapy
OpenAlex ID: W4399772948