Cheng Ma1 & Jenny KW Lam2
1Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China
2UCL School of Pharmacy, University College London, London, United Kingdom
Summary
The messenger RNA (mRNA) therapeutic strategy has garnered significant interest and attention for treating pulmonary diseases, owing to its potential to address various respiratory conditions effectively. PEG12KL4 is a cationic peptide that has demonstrated promising mRNA transfection capabilities in previous studies; however, it still faces notable challenges related to its ability to penetrate and transfect through the pulmonary mucus layer, which acts as a substantial barrier in pulmonary delivery. Lipid nanoparticles (LNPs) are among the most commonly used formulations for achieving efficient mRNA transfection in clinical applications. Nonetheless, it is reported that they are not stable enough to preserve the transfection efficiency of mRNA after nebulisation, which is critical for inhalation-based therapies. To address these issues, this study combined PEG12KL4 and LNP formulations to investigate their stability during nebulisation and their transfection capabilities in the presence of artificial mucus. The results indicated that LNPs containing PEG12KL4 exhibited improved transfection efficiency in artificial mucus compared to the complex formulations without PEG12KL4. Among the tested formulations, the LNPs containing 10% PEG12KL4 (P10NP3) demonstrated the highest stability to nebulisation within the LNPs formulations, revealing their robustness during aerosolisation and their potential for effective pulmonary mRNA delivery. These findings underscore the promising application of PEG12KL4-containing LNP formulations for advancing pulmonary mRNA therapeutics, offering a viable strategy to overcome mucus barrier challenges and improve transfection efficiency in respiratory treatments.