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<p>Messenger RNA (mRNA) therapeutics are a promising strategy to combat diverse diseases. Traditional lipid nanoparticle (LNP) formulations for mRNA delivery contain poly(ethylene) glycol (PEG), a polymer widely used in drug delivery carriers but that recently has been associated with efficacy and immunogenicity concerns. Here we report poly(carboxybetaine) (PCB) lipids as surrogates for PEG-lipids used in mRNA formulations. In vitro studies with immortalized and primary cells show that PCB-containing LNPs have higher mRNA transfection efficiency than PEG-containing LNPs across different formulations. Moreover, primary cell engineering and in vivo immunization studies in mice further demonstrate greater therapeutic efficacy of PCB-containing LNPs over their PEG counterparts. Mechanistic assays show that this improvement is attributed to enhanced endosomal escape of PCB-containing LNPs. These formulations exhibit a safe immunotoxicity profile and effectively mitigate the accelerated blood clearance effect that has been observed for PEG-containing LNPs, enabling repeated administrations without efficacy loss. Overall, these findings highlight PCB-containing LNPs as a potent and safe mRNA delivery platform for clinical applications.</p>

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Poly(carboxybetaine) lipids enhance mRNA therapeutics efficacy and reduce their immunogenicity

  • 期刊论文

  • 发表日期：

    2025年5月29日

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  • Sijin Luozhong,
  • Pingchuan Liu,
  • Ruoxin Li,
  • Zhefan Yuan,
  • Erica Debley,
  • Yu Chen,
  • Yuping Hu,
  • Zeyu Cao,
  • Meng Cui,
  • Kay McIlhenny,
  • Caleb McCurdy,
  • Dani Bhashyam,
  • Stephan Wilkens,
  • Prince Zhang,
  • Austin Kwan,
  • Mark Grossman,
  • Rachel Lai,
  • Yufei Ma,
  • Steven Lipkin,
  • Shaoyi Jiang

摘要

Messenger RNA (mRNA) therapeutics are a promising strategy to combat diverse diseases. Traditional lipid nanoparticle (LNP) formulations for mRNA delivery contain poly(ethylene) glycol (PEG), a polymer widely used in drug delivery carriers but that recently has been associated with efficacy and immunogenicity concerns. Here we report poly(carboxybetaine) (PCB) lipids as surrogates for PEG-lipids used in mRNA formulations. In vitro studies with immortalized and primary cells show that PCB-containing LNPs have higher mRNA transfection efficiency than PEG-containing LNPs across different formulations. Moreover, primary cell engineering and in vivo immunization studies in mice further demonstrate greater therapeutic efficacy of PCB-containing LNPs over their PEG counterparts. Mechanistic assays show that this improvement is attributed to enhanced endosomal escape of PCB-containing LNPs. These formulations exhibit a safe immunotoxicity profile and effectively mitigate the accelerated blood clearance effect that has been observed for PEG-containing LNPs, enabling repeated administrations without efficacy loss. Overall, these findings highlight PCB-containing LNPs as a potent and safe mRNA delivery platform for clinical applications.