Lung-selective mRNA delivery of synthetic lipid nanoparticles for the treatment of pulmonary lymphangioleiomyomatosis

Abstract

Safe and efficacious systemic delivery of messenger RNA (mRNA) to specific organs and cells in vivo remains the major challenge in the development of mRNA-based therapeutics. Targeting of systemically administered lipid nanoparticles (LNPs) coformulated with mRNA has largely been confined to the liver and spleen. Using a library screening approach, we identified that N-series LNPs (containing an amide bond in the tail) are capable of selectively delivering mRNA to the mouse lung, in contrast to our previous discovery that O-series LNPs (containing an ester bond in the tail) that tend to deliver mRNA to the liver. We analyzed the protein corona on the liver- and lung-targeted LNPs using liquid chromatography–mass spectrometry and identified a group of unique plasma proteins specifically absorbed onto the surface that may contribute to the targetability of these LNPs. Different pulmonary cell types can also be targeted by simply tuning the headgroup structure of N-series LNPs. Importantly, we demonstrate here the success of LNP-based RNA therapy in a preclinical model of lymphangioleiomyomatosis (LAM), a destructive lung disease caused by loss-of-function mutations in the Tsc2 gene. Our lung-targeting LNP exhibited highly efficient delivery of the mouse tuberous sclerosis complex 2 (Tsc2) mRNA for the restoration of TSC2 tumor suppressor in tumor and achieved remarkable therapeutic effect in reducing tumor burden. This research establishes mRNA LNPs as a promising therapeutic intervention for the treatment of LAM.

Anti-PEG Antibodies Boosted in Humans by SARS-CoV-2 Lipid Nanoparticle mRNA Vaccine

“…Plasma proteins are known to opsonize foreign nanomaterials in the blood, forming so-called “biomolecular coronas”, − which leads to recognition and inactivation of nanomaterials by the immune system. − The formation of biomolecular coronas on Doxil in vivo in human systemic circulation has been previously described . Recently, the composition of biomolecular coronas was also found to regulate fate and/or utility of LNPs. , In our previous studies, we found that the enrichment of immunoglobulins and complement proteins in biomolecular coronas is correlated with donor-specific nanoparticle association with human blood immune cells . The studies herein demonstrate that anti-PEG antibodies are probably one of the key immunoglobulins that drive the donor-dependent immune cell association of PEG-containing nanoparticles in human blood.…”

Delivery of Circular mRNA via Degradable Lipid Nanoparticles against SARS-CoV-2 Delta Variant

“…However, significant luciferase fluorescence was only observed in the whole liver ( Figures 3A-C ), signifying the liver-targeted protein expression of mRNA-AX4-LNP. It is well known that the liver-targeting LNP acquired of ApoE in the serum results in uptake of lipoproteins by liver hepatocytes through receptor-mediated endocytosis by low-density lipoprotein receptor (LDL-R) [10, 14] . To explore whether the endogenous ApoE affects the protein expression level of mRNA-AX4-LNP in different organs, a ApoE knockout (ApoE - / - ) mouse model was employed.…”

Anti-PEG Antibodies Boosted in Humans by SARS-CoV-2 Lipid Nanoparticle mRNA Vaccine

“…22 Recently, the composition of biomolecular coronas was also found to regulate fate and/or utility of LNPs. 28,29 In our previous studies we found that the enrichment of immunoglobulins and complement proteins in biomolecular coronas is correlated with donor-specific nanoparticle association with human blood immune cells. 19 The studies herein demonstrate that anti-PEG antibodies are key immunoglobulins that drive the donor-dependent immune cell association of PEG-containing nanoparticles in human blood.…”