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<p>Lipid nanoparticles (LNPs) have enabled the effective delivery of RNA therapeutics and mRNA vaccines. However, their broader applications are limited by suboptimal stability and endosomal escape efficiency. Here we present a readily adoptable post-assembly crosslinking approach that enhances the structural and functional stability of mRNA LNPs. By leveraging a series of cholesterol derivatives and crosslinking methods, we induce crosslinks between the lipid components following mRNA LNP assembly, forming crosslinked LNPs (cLNPs). We systematically evaluated crosslinking parameters and identified the optimal conditions that enhance both the physical stability and transfection efficiency of cLNPs. Our findings demonstrate that cLNPs exhibit improved structural integrity under storage and lyophilization conditions, and increased extracellular stability and endosomal escape efficiency, resulting in improved performance of mRNA LNPs both in vitro and in vivo. This crosslinking strategy enables more resilient formulations and expands the applicability of LNP-based therapies for gene therapy and vaccine delivery. Our work lays the foundation for next-generation LNPs with enhanced stability and delivery efficiency, amplifying the impact of RNA therapeutics and vaccines.</p><p></p>

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Crosslinking of lipid nanoparticles enhances the delivery efficiency and efficacy of mRNA vaccines

  • 期刊论文

  • 发表日期：

    2026年2月16日

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  • Xiang Liu,
  • Yining Zhu,
  • Christine Wei,
  • Jinghan Lin,
  • Di Yu,
  • Jiayuan Kong,
  • Fangchi Shao,
  • Jingyao Ma,
  • Tian Xu,
  • Xiaoya Lu,
  • Yunhe Su,
  • Kailei D. Goodier,
  • Leonardo Cheng,
  • Wu Han Toh,
  • Christopher J. Erb,
  • Sixuan Li,
  • Tza-Huei Wang,
  • Hai-Quan Mao

摘要

Lipid nanoparticles (LNPs) have enabled the effective delivery of RNA therapeutics and mRNA vaccines. However, their broader applications are limited by suboptimal stability and endosomal escape efficiency. Here we present a readily adoptable post-assembly crosslinking approach that enhances the structural and functional stability of mRNA LNPs. By leveraging a series of cholesterol derivatives and crosslinking methods, we induce crosslinks between the lipid components following mRNA LNP assembly, forming crosslinked LNPs (cLNPs). We systematically evaluated crosslinking parameters and identified the optimal conditions that enhance both the physical stability and transfection efficiency of cLNPs. Our findings demonstrate that cLNPs exhibit improved structural integrity under storage and lyophilization conditions, and increased extracellular stability and endosomal escape efficiency, resulting in improved performance of mRNA LNPs both in vitro and in vivo. This crosslinking strategy enables more resilient formulations and expands the applicability of LNP-based therapies for gene therapy and vaccine delivery. Our work lays the foundation for next-generation LNPs with enhanced stability and delivery efficiency, amplifying the impact of RNA therapeutics and vaccines.