Synthetic Poly(2-Oxazoline) Chimera 'Lipo-Polymers' as Replacements for Key Lipids in Lipid Nanoparticles

Abstract

Lipid nanoparticles (LNPs) rely on specialized lipid components, many of which are proprietary and difficult to access or modify. Here, we introduce a polymer-based alternative to key LNP constituents through the development of chimera poly(2-oxazoline) (POx) synthetic lipid polymers (SLPs) and synthetic lipid oligomers (SLOs). These chimeric lipid-mimetic materials are designed for seamless incorporation into existing LNP architectures, enabling direct replacement of PEG-lipid conjugates and ionizable lipids, respectively. Chimeric SLPs comprise hydrophilic shell-forming POx blocks linked to hydrophobic lipid-inserting domains, whereas SLOs consist of hydrophobic POx oligomers terminated with ionizable amine-containing groups. Using mRNA-loaded LNPs, we demonstrate that first-generation POx-Chimera SLPs and SLOs functionally replace industry-standard lipid components while maintaining robust transfection activity in vitro and in vivo. Notably, SLO-containing formulations achieved expression levels comparable to, and in some cases exceeding, those of conventional lipid formulations. Together, these results establish POx-Chimera SLPs and SLOs as a versatile platform for polymer-centric LNP engineering, creating new opportunities to tune nanoparticle composition, biodistribution, and transgene expression while reducing reliance on proprietary lipids.