Rayleigh-based soft mist inhalers preserve mRNA-LNP integrity for pulmonary delivery

Pulmonary delivery of mRNA-lipid nanoparticles (mRNA-LNPs) offers a promising non-invasive route of administration for pulmonary gene therapy, vaccine applications, amongst others. However, aerosolisation can compromise nanoparticle stability, affecting its payload and thus delivery efficiency. This study evaluates the impact of aerosolisation via Rayleigh breakup and Savart impinging jet-based soft mist inhalers (SMIs) and various mesh nebulisers in preserving mRNA-LNP integrity and thus optimising pulmonary deposition. The pre-filled syringe inhaler (PFSI, Resyca) and Respimat (Boehringer Ingelheim) SMIs, as well as the Innospire Go and Pari eFlow mesh nebulisers were assessed for their impact on LNP particle size, zeta potential, encapsulation efficiency, and mRNA stability. The PFSI SMI maintained mRNA-LNP physicochemical properties with minimal aggregation and superior encapsulation efficiency, while the other devices induced significant particle alterations and mRNA degradation. These findings highlight the potential of SMIs, particularly the PFSI device, for inhaled mRNA-LNP delivery. Its ability to maintain nanoparticle stability warrants clinical evaluation.