Lipid nanoparticles (LNPs) are delivery vehicles for currently two widely used mRNA COVID-19 vaccines. It has also shown good results in delivering genetic information to the liver. However, precise delivery of packaged "goods" into tissues other than the liver remains a challenge. In a recent paper published recently in the Proceedings of the National Academy of Sciences (PNAS), Dr. Qiaobing Xu's group in the Department of Bioengineering at Tufts University, along with partners at Harvard University and the University of Massachusetts, have developed LNPs that can precisely deliver mRNA to lung tissue. The therapy of mRNA delivered by LNPs significantly reduced the disease burden of lymphangioleiomyomatosis in animal models.
It has been shown that by altering the structure of the lipid molecules that make up LNP, the specificity of their tissue targeting can be changed. By screening the library of lipid molecular compounds, Dr. Xu's research group found a series of lipid molecules with amide bonds at the tail of the lipid molecule, which constitute LNPS that have the ability to selectively deliver mRNA to the lungs of mice.
Further research found that when lung-targeting LNPs enter the bloodstream, they cause specific plasma proteins to attach to the surface of LNPs, giving them the ability to target lung tissue. The researchers identified 14 proteins, including ApoE, albumin, fibrinogen β and fibrinogen γ, that may contribute to specific absorption of LNPs in the lungs by liquid chromatography-mass spectrometry.
To further verify the role of LNPs, the researchers used it to deliver mRNA encoding the normal Tsc2 gene to mice with lymphangioleiomyomatosis due to an inactivating mutation in the Tsc2 gene. The experimental results show that this LNP can highly efficiently deliver Tsc2 mRNA into lung cells, restore Tsc2 function, and significantly reduce tumor burden in mice.
mRNA can be delivered to lung tissue by aerosol inhalation. If administered intravenously, the drug must avoid liver clearance, continuously interact with lung endothelial cells, and cross the basement membrane into other types of lung cells. In contrast, for aerosol inhalation, the drug must diffuse through mucus and avoid phagocytosis by specialized lung immune cells. Optimizing a systemic mRNA delivery system differs from optimizing a nebulized drug delivery system due to differences in delivery barriers. For example, the researchers optimized the delivery of atomized LNP-mRNA, and the resulting LNP [called Nebulized Lung Delivery 1 (NLD1)] could deliver significantly more mRNA to the lungs than previously optimized LNPs for systemic delivery. Therapeutic mRNA encoding the antibody was also delivered to protect mice from lethal influenza.
After systemic administration, mRNA can also be delivered to the lungs. A key finding shows that by adding cationic lipids to common liver-targeting LNPs, two groups independently demonstrated that these LNPs can be retargeted to the lungs. The first group of researchers added the permanent cationic lipid DOTAP to LNPs containing the degradable dendrimer ionizable lipid 5A2-SC8, DLin-MC3-DMA or the ionizable lipid C12-200, results showed that LNPs containing 50% DOTAP could effectively modulate lung-specific delivery, and that neither LNP required active targeting ligands such as antibodies, peptides, or aptamers.
LNP is a highly individually designed nucleic acid delivery vehicle that shows great potential in mRNA vaccine delivery. In addition, the potential value of LNPs in rare disease and cancer therapy cannot be ignored. mRNA therapy can help produce therapeutic proteins to restore the function of damaged tissues or organs.
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 Targeting gene therapy directly into the lungs. Retrieved February 23, 2022, from https://medicalxpress.com/news/2022-02-gene-therapy-lungs.html
 Qiu et al., (2022). Lung-selective mRNA delivery of synthetic lipid nanoparticles for the treatment of pulmonary lymphangioleiomyomatosis. PNAS, https://doi.org/10.1073/pnas.2116271119
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