(641g) Super-Hydrophilic Polymer Modification of Lipid Nanoparticles for Inhaled Delivery of mRNA

Lipid nanoparticles (LNPs) are safe and effective for the delivery of mRNA vaccines. However, their use for inhaled delivery of mRNA to treat a wide variety of pulmonary diseases has been limited by the challenge of nebulizing LNPs. Nebulization of LNPs causes LNPs to aggregate and release encapsulated mRNA, limiting their delivery efficacy. This suggests that traditional PEG polymer modifications of LNP surfaces, which are included to improve colloidal stability of LNPs, are insufficient for fully stabilizing LNPs to nebulization. Additionally, growing concerns over anti-PEG antibodies which may limit LNP efficacy have sparked growing interest in PEG-polymer alternatives for modifying LNP surfaces.

Here, we report the development of LNPs whereby the PEG-lipid is fully replaced with a super-hydrophilic polymer (SHP)-lipid conjugate to substantially stabilize LNPs to nebulization and improve inhaled mRNA delivery. LNPs formulated with SHP-lipids (SHP-LNPs) resisted aggregation and had minimal loss of encapsulated mRNA during nebulization. A SHP-LNP formulation optimized through design of experiment screening methodologies demonstrated improved inhaled mRNA delivery in both healthy and muco-obstructed mouse lungs. Repeat administration of the optimized SHP-LNP formulation was well tolerated and did not result in pulmonary inflammation. This study demonstrates the potential of super-hydrophilic polymer-lipid conjugates for improving the clinical translatability of inhaled mRNA-LNP formulations.