MicroRNAs (miRs) are
small noncoding RNA sequences that negatively regulate the expression of target genes by posttranscriptional repression. miRs are dysregulated in various diseases, including
cancer. let-7a miR, an antioncogenic miR, is downregulated in
lung cancers. Our earlier studies demonstrated that let-7a miR inhibits
tumor growth in
malignant pleural mesothelioma (MPM) and could be a potential therapeutic against
lung cancer. EphA2 (
ephrin type-A receptor 2)
tyrosine kinase is overexpressed in most
cancer cells, including MPM and
non-small-cell lung cancer (NSCLC) cells.
Ephrin-A1, a specific
ligand of the
EphA2 receptor, inhibits cell proliferation and migration. In this study, to enhance the delivery of miR, the miRs were encapsulated in the
DOTAP (N-[1-(2.3-dioleoyloxy)propyl]-N,N,N-trimethyl
ammonium)/
Cholesterol/
DSPE (1,2-distearoyl-sn-glycero-3-
phosphoethanolamine-N-[cyanur(
polyethylene glycol)-2000])-PEG (
polyethylene glycol)-cyanur liposomal nanoparticles (LNP) and
ephrin-A1 was conjugated on the surface of LNP to target
receptor EphA2 on
lung cancer cells. The LNP with an average diameter of 100 nm showed high stability, low cytotoxicity, and high loading efficiency of precursor let-7a miR and
ephrin-A1. The
ephrin-A1 conjugated LNP (ephrin-A1-LNP) and let-7a miR encapsulated LNP (miR-LNP) showed improved transfection efficiency against MPM and NSCLC. The effectiveness of targeted delivery of let-7a miR encapsulated
ephrin-A1 conjugated LNP (miR-ephrin-A1-LNP) was determined on MPM and NSCLC
tumor growth in vitro. miR-ephrin-A1-LNP significantly increased the delivery of let-7a miR in
lung cancer cells when compared with free let-7a miR. In addition, the expression of target gene Ras was significantly repressed following miR-ephrin-A1-LNP treatment. Furthermore, the miR-ephrin-A1-LNP complex significantly inhibited MPM and NSCLC proliferation, migration, and
tumor growth. Our results demonstrate that the engineered miR-ephrin-A1-LNP complex is an effective carrier for the targeted delivery of small
RNA molecules to
lung cancer cells. This could be a potential therapeutic approach against
tumors overexpressing the
EphA2 receptor.