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<p>Messenger RNA (mRNA) therapeutics rely on lipid nanoparticles (LNPs) for delivery, yet inefficient endosomal escape remains a major bottleneck, with only a small fraction of internalized cargo reaching the cytoplasm. Conventional LNPs encapsulate mRNA in amorphous lipid cores, where partial charge neutralization and lack of structural order limit protonation-driven membrane disruption. Here, we present an architectural strategy that engineers LNP internal structure using ionizable lipid–coated gold nanoparticles (IC-AuNPs) as rigid, pH-responsive cores. The Au cores template the formation of radially ordered core–shell architectures that stabilize particles at physiological pH while amplifying charge segregation and curvature stress under acidic endosomal conditions. As a result, Au-LNPs achieve a twofold increase in endosomal escape and ~100-fold greater cytoplasmic mRNA diffusion compared to conventional LNPs. Functionally, Au-LNPs enhance mRNA expression in vitro, increases in vivo protein production up to sevenfold, boost antibody responses to SARS-CoV-2 vaccines, and improve therapeutic efficacy in a triple-negative breast cancer model.</p>

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Engineered internal architecture of core-shell lipid nanoparticles promotes efficient mRNA endosomal release

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月30日

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  • Tianyao Li,
  • Jingxin Zhang,
  • Jing Guo,
  • Bohong Sun,
  • Yuxuan Han,
  • Hu Xu,
  • Yi Weng,
  • Qinghao Cao,
  • Min Li,
  • Guangyu Zhao,
  • Lin Liu,
  • Xingfa Gao,
  • Lianpan Dai,
  • Daming Wang,
  • Yuhong Cao

摘要

Messenger RNA (mRNA) therapeutics rely on lipid nanoparticles (LNPs) for delivery, yet inefficient endosomal escape remains a major bottleneck, with only a small fraction of internalized cargo reaching the cytoplasm. Conventional LNPs encapsulate mRNA in amorphous lipid cores, where partial charge neutralization and lack of structural order limit protonation-driven membrane disruption. Here, we present an architectural strategy that engineers LNP internal structure using ionizable lipid–coated gold nanoparticles (IC-AuNPs) as rigid, pH-responsive cores. The Au cores template the formation of radially ordered core–shell architectures that stabilize particles at physiological pH while amplifying charge segregation and curvature stress under acidic endosomal conditions. As a result, Au-LNPs achieve a twofold increase in endosomal escape and ~100-fold greater cytoplasmic mRNA diffusion compared to conventional LNPs. Functionally, Au-LNPs enhance mRNA expression in vitro, increases in vivo protein production up to sevenfold, boost antibody responses to SARS-CoV-2 vaccines, and improve therapeutic efficacy in a triple-negative breast cancer model.