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<p>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.</p>

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Polypeptide-engineered lipid nanoparticles for mRNA delivery with limited immunogenicity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • Jin-Yue Zeng,
  • Yue Zhang,
  • Gui Zhao,
  • Brandon Yi Loong Seow,
  • Nithiyaa Bala Krishnan,
  • Jin Hao Goh,
  • Yi Yan Yang

摘要

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.