Zeng, J.-Y., Zhang, Y., Zhao, G., Seow, B. Y. L., Krishnan, N. B., Goh, J. H., & Yang, Y. Y. (2026). Polypeptide-engineered lipid nanoparticles for mRNA delivery with limited immunogenicity. Nature Communications. https://doi.org/10.1038/s41467-026-73698-6
Abstract:
Abstract
Lipid nanoparticles (LNPs) have shown great potential for mRNA delivery, with polyethylene glycol (PEG) lipids playing a critical role in modulating particle size, stability and biodistribution. However, most PEGylated LNPs induce anti-PEG antibodies, leading to hypersensitivity and diminished efficacy upon repeated administration. Here we report hydrophilic, nonionic and biodegradable poly(D, L-serine) (pDLS) lipids as PEG-lipid alternatives in LNP formulations. Through systematic structural screening, we identify optimal lipid architectures that yield colloidally stable pDLS-LNPs with high mRNA encapsulation and transfection efficiency. Compared to the clinically approved BNT162b2 formulation (ALC-LNP), pDLS-LNPs loaded with SARS-CoV-2 spike mRNA achieve superior mRNA delivery, and elicit robust cellular and humoral immune responses in mice, without inducing systemic toxicity. Notably, repeated dosing with pDLS-LNPs triggers minimal anti-pDLS IgM production, unlike PEG-based counterparts. Furthermore, pDLS-LNPs remain stable under frozen storage for over 6 months. These findings establish polypeptide-based pDLS-LNPs as promising, immunologically inert alternatives to PEGylated LNPs for safe and effective mRNA delivery.
License type:
Attribution 4.0 International (CC BY 4.0)
Funding Info:
This research / project is supported by the A*STAR - Industry Alignment Fund - Pre-Positioning
Grant Reference no. : H22J1a0050
This research / project is supported by the National Research Foundation - Competitive Research Programme
Grant Reference no. : CRP27-2021-0038