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<p>Organ-selective delivery of messenger RNA (mRNA) is critical for fulfilling the therapeutic potential of mRNA-based gene and protein replacement technologies. Despite clinical advances in the hepatic delivery of mRNA using lipid nanoparticles (LNPs), current strategies for extrahepatic-organ-selective mRNA delivery still have limitations. Here we report a peptide-encoded organ-selective targeting (POST) method for the delivery of mRNA to extrahepatic organs after systemic administration, which is based on the modular tuning of LNPs through surface engineering with specific amino acid sequences (POST codes). Molecular dynamics simulations and in vitro and in vivo testing show that the organ-selective targeting of POST results from the specific protein corona of the peptide-decorated LNPs, which is established from the mechanical optimization of the binding affinities between peptides with a particular sequence and plasma proteins. This approach can be used for the organ-selective delivery of different ribonucleic acids and multiple gene editing machinery. Overall, the POST platform creates a modular repertoire for LNP surface engineering for directing organ tropism, broadening the scope and versatility of organ-selective delivery.</p>

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Peptide codes for organ-selective mRNA delivery

  • 期刊论文

  • 发表日期：

    2025年9月1日

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  • Tie Chang,
  • Yifan Zheng,
  • Mingrui Jiang,
  • Siqi Jia,
  • Jianbo Bai,
  • Zhi Zheng,
  • Shixin Li,
  • Jia Guo,
  • Yue Wang,
  • Yiting Wang,
  • Haixia Liu,
  • Jianlin Liu,
  • Liangyu Ni,
  • Xingdi Cheng,
  • Shuai Liu,
  • Huijuan Zhang,
  • Wei Pi,
  • Feng Lin,
  • Shiyi Liu,
  • Weijian Wang,
  • Guannan Wang,
  • Leyun Wang,
  • Lei Miao,
  • Xueguang Lu,
  • Ziqing Deng,
  • Bing Bai,
  • Zhao Qin,
  • Huajian Gao,
  • Yue Shao

摘要

Organ-selective delivery of messenger RNA (mRNA) is critical for fulfilling the therapeutic potential of mRNA-based gene and protein replacement technologies. Despite clinical advances in the hepatic delivery of mRNA using lipid nanoparticles (LNPs), current strategies for extrahepatic-organ-selective mRNA delivery still have limitations. Here we report a peptide-encoded organ-selective targeting (POST) method for the delivery of mRNA to extrahepatic organs after systemic administration, which is based on the modular tuning of LNPs through surface engineering with specific amino acid sequences (POST codes). Molecular dynamics simulations and in vitro and in vivo testing show that the organ-selective targeting of POST results from the specific protein corona of the peptide-decorated LNPs, which is established from the mechanical optimization of the binding affinities between peptides with a particular sequence and plasma proteins. This approach can be used for the organ-selective delivery of different ribonucleic acids and multiple gene editing machinery. Overall, the POST platform creates a modular repertoire for LNP surface engineering for directing organ tropism, broadening the scope and versatility of organ-selective delivery.