Optimisation of peptide-LNPs for pulmonary mRNA delivery - elucidating the effect of nebulisation on the structural integrity of peptide-LNPs by neutron scattering

mRNA therapeutics show strong potential for lung disease treatment, but their clinical use is limited by the lack of efficient delivery systems for inhalation. While lipid nanoparticles (LNPs) are the leading platform, their stability is compromised during nebulisation, leading to reduced efficacy. We previously developed a PEG12KL4 peptide that enables stable mRNA delivery post-nebulisation, but its cationic nature limits mucus penetration. In this study, we replace the PEG-lipid in LNPs with PEG12KL4 peptide to improve both mucus penetration and aerosol stability. Using a Moderna-based LNP formulation, PEG12KL4-modified LNPs (P-LNPs) maintained size after nebulisation, enhanced transfection in mucus-rich conditions, and outperformed standard LNPs post-nebulisation. The overall aim of this study is to analyse investigate the structural characteristics of the P-LNP system at various formulations and monitor the structural stability during nebulisation. The outcomes of the study would provide valuable insights that allow us to optimise and tailor a P-LNP system applicable for inhaled RNA therapy in patients with chronic lung conditions.