Messenger RNA (mRNA) has considerable potential as therapy for a range of lung diseases. Pulmonary delivery of mRNA is particularly attractive as it could maximize the concentration of mRNA therapeutics in the lung and minimize systemic side effects. A safe and effective delivery vector of mRNA is required to mediate robust transfection. Here, we introduce a novel RNA delivery vector, PEG12KL4, in which the synthetic cationic KL4 peptide is modified by attaching to a monodisperse linear PEG of 12-mers to increase the solubility of the peptide. mRNA was bound to KL4 and PEG12KL4 at 2:1 and 2.5:1 ratio (w/w), respectively. The PEG12KL4/mRNA complexes could mediate effective transfection on human lung epithelial cells, and performed significantly better than the KL4 peptide. Moreover, the PEG12KL4/mRNA complexes did not induce significant expression of inflammatory cytokines in human lung epithelial cells. Overall, PEG12KL4 is an excellent mRNA transfection agent for pulmonary delivery with high transfection efficiency and low immunogenicity.
Delivery is a major barrier for the development of mRNA therapeutics. In this study, a safe and efficient peptide based delivery system, PEG12KL4 was developed. The PEG12KL4 could mediate high transfection of the mRNA on lung epithelial cells with no sign of immunogenicity.