Synthetic Poly(2-Oxazoline) Chimera 'Lipo-Polymers' as Replacements for Key Lipids in Lipid Nanoparticles
- 1Department of Surgery, Duke University Medical Center, Durham, NC, 27710, USA
- 2Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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.
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BibTeX
@misc{ramsey2026synthetic,
title = {{Synthetic Poly(2-Oxazoline) Chimera 'Lipo-Polymers' as Replacements for Key Lipids in Lipid Nanoparticles}},
author = {Jacob D. Ramsey and Matthew J. Haney and Yuling Zhao and Hallie Hutsell and Alexander V. Kabanov},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.23.761445},
url = {https://www.biorxiv.org/content/10.64898/2026.10.23.761445v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Synthetic Poly(2-Oxazoline) Chimera 'Lipo-Polymers' as Replacements for Key Lipids in Lipid Nanoparticles
AU - Jacob D. Ramsey
AU - Matthew J. Haney
AU - Yuling Zhao
AU - Hallie Hutsell
AU - Alexander V. Kabanov
PY - 2026
DA - 2026/10/23
PB - bioRxiv
DO - 10.64898/2026.10.23.761445
UR - https://www.biorxiv.org/content/10.64898/2026.10.23.761445v1
AB - 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.
SN - 2692-8205
ER -