PBAE-PEG/Lipid Nanoparticle Delivery of RNA for the Creation of Genetically Engineered Lung Cancer Mouse Models.

Abstract

We have recently developed polymer/lipid nanoparticles PBAE-PEG/4A3-SC8/DOPE/Cholesterol/DOTAP (hereafter, PBAE-PEG/LNP) that can deliver mRNA into lung cells. Here, using PBAE-PEG/LNP, we deliveredmRNA and/or sgRNAs intoand/ormice to develop genetically engineered lung cancer mouse models. PBAE-PEG/LNP delivery ofmRNA intomice by intratracheal (IT) injection produced autochthonous lung tumors while intravenous injection resulted in lung tumors as well as bronchus-associated lymphoid tissue (BALT). PBAE-PEG/LNP delivery ofmRNA along with sgRNA targeting the lung lineage transcription factor(sgNkx2-1) intomice by IT injection produced autochthonous invasive mucinous adenocarcinoma of the lung (IMA) that lacks NKX2-1 while expressing the gastrointestinal transcription factor HNF4A. PBAE-PEG/LNP delivery of sgRNAs targeting(sgEml4) and(sgAlk) intomice by IT injection produced autochthonous lung tumors carrying the driver oncogene. This approach using PBAE-PEG/LNP to deliver RNA will allow for agile development of lung cancer mouse models.