Progress in Lipid Nanoparticle Technology

Lipid nanoparticles (LNPs) are widely used as delivery vehicles for mRNA based COVID-19 vaccines. It has also shown good results in transmitting genetic information to the liver. However, accurately delivering packaged 'goods' to tissues outside of the liver remains a huge challenge. In a recent paper published in the Proceedings of the National Academy of Sciences (PNAS), Dr. Xu's team, along with partners from Harvard University and the University of Massachusetts, developed LNPs that can be precisely delivered to lung tissue. The treatment of mRNA transmitted through LNPs significantly reduced the disease burden of lymphangioleiomyomatosis in animal models.

Research has shown that by altering the structure of lipid molecules that make up LNP, its tissue targeting specificity can be changed. Through screening the lipid molecule compound library, Dr. Xu's research team discovered a series of lipid molecules with amide bonds at the tail of the lipid molecules, forming LNPS, which has the ability to selectively deliver mRNA to mouse lungs.

Further research has found that when lung targeted LNPs enter the bloodstream, they cause specific plasma proteins to adhere to the surface of LNPs, giving them the ability to target lung tissue. Researchers identified 14 proteins, including ApoE, albumin, fibrinogen beta, and fibrinogen gamma, which may contribute to the specific absorption of LNPs in the lungs through liquid chromatography-mass spectrometry analysis.

To further validate the role of LNPs, researchers used it to deliver mRNA encoding the normal Tsc2 gene to mice with lymphangioleiomyomatosis caused by Tsc2 gene inactivation mutations. The experimental results indicate that the LNP can efficiently deliver Tsc2 mRNA into lung cells, restore Tsc2 function, and significantly reduce tumor burden in mice.

MRNA can be delivered to lung tissue through aerosol inhalation. If administered intravenously, the drug must avoid being cleared by the liver, continue to interact with lung endothelial cells, and penetrate the basement membrane into other types of lung cells. In contrast, for aerosol inhalation, drugs must diffuse through mucus and avoid being engulfed by specialized lung immune cells. Due to differences in delivery barriers, optimizing mRNA delivery systems is different from optimizing nebulized drug delivery systems. For example, researchers optimized the delivery of nebulized LNP mRNA, resulting in an LNP called nebulized lung delivery 1 (NLD1) that can deliver more mRNA than previously optimized LNP. The therapeutic mRNA encoding this antibody is also used to protect mice from lethal influenza infection.

After systemic administration, mRNA can also be transported to the lungs. A key finding suggests that by adding cationic lipids to common liver targeted LNPs, two groups of researchers independently demonstrated that these LNPs can be repositioned to the lungs. The first group of researchers added cationic lipids DOTAPLNPs containing degradable dendritic molecules, ionizable lipids 5A2-SC8, DLin-MC3-DMA, or ionizable lipids C12-200. The results showed that LNPs containing 50% DOTAP can effectively regulate lung specific delivery, and LNPs require active target ligands such as antibodies, peptides, or aptamers.

LNP is a highly individually designed nucleic acid delivery vector that has shown great potential in mRNA vaccine delivery. In addition, the potential value of LNPs in the treatment of rare diseases and cancer cannot be ignored. MRNA therapy can help generate therapeutic proteins to restore the function of damaged tissues or organs.

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