Cyclic Poly(2-methyl-2-oxazoline)-Lipid Conjugates Are Good Alternatives to Poly(ethylene glycol)-Lipids for Lipid Nanoparticle mRNA Formulation.

Lipid nanoparticles (LNPs) with ionizable cationic lipids have revolutionized RNA drug delivery, playing a key role in the success of mRNA-based therapeutics, such as COVID-19 vaccines. A vital component of these LNPs is the poly(ethylene glycol) (PEG)-lipid conjugate, which enhances colloidal stability but may trigger the production of anti-PEG antibodies, resulting in accelerated blood clearance (ABC) and diminished therapeutic efficacy. In this study, we explored poly(2-methyl-2-oxazoline) (PMOXA) as an alternative stabilizing agent for mRNA LNPs. We synthesized both cyclic and linear PMOXA, conjugated them to dialkyl lipids, and created lipid-polymer amphiphiles. We systematically evaluated how polymer topology influenced the physicochemical properties of LNPs, including in vitro cellular uptake, transfection efficiency, and protein corona formation, and directly compared these properties with those of PEG-stabilized counterparts. In vivo experiments in mice further assessed the biodistribution and protein translation efficiency of these LNPs following intravenous administration. Our results showed that cyclic PMOXA conjugates not only matched but potentially surpassed the performance of PEG-based analogues, highlighting their promise as a superior alternative in mRNA-LNP formulations.