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<p>In vivo genetic engineering of haematopoietic stem and progenitor cells (HSPCs) holds the potential to revolutionize the treatment landscape for numerous diseases. However, despite its transformative potential, it remains hindered by the difficulty in efficiently and specifically targeting quiescent human HSCs while maintaining their long-term functionality. Here, after screening 15 lipid nanoparticles (LNPs), we report an LNP that efficiently delivers reporter mRNA to human HSPCs both in ex vivo and in vivo settings when conjugated with the anti-CD34 antibody (CD34/LNP<sup>DP</sup>). Using CRISPR/Cas editing cargos, CD34/LNP<sup>DP</sup> achieves high editing efficiency in human HSPCs ex vivo. Intrafemoral administration of CD34/LNP<sup>DP</sup> in humanized mice results in efficient editing of the erythroid-specific <i>BCL11A</i> enhancer within human HSPCs, enabling the sustained long-term reactivation of fetal haemoglobin (HbF) expression in erythroid cells. In a humanized neutropaenia model harbouring an <i>ELANE</i> mutation, intrafemoral administration of CD34/LNP<sup>DP</sup> achieves robust editing, targeting exon 2 of <i>ELANE</i> in human HSPCs, partially restoring neutrophil development impairment under long-term observation. Collectively, CD34-targeted delivery enables in vivo HSPC modification without perturbing haematopoiesis, underscoring its suitability for clinical translation.</p>

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Engineered lipid nanoparticles for in vivo and durable editing of haematopoietic stem cells within humanized mice

  • 期刊论文

  • 发表日期：

    2026年8月5日

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  • Jingjing Du,
  • Zijin Luo,
  • Dan Xie,
  • Yan Chen,
  • Ming Yang,
  • Qiang Li,
  • Lisha Wang,
  • Lu Han,
  • Yiming Zhang,
  • Haiwei Li,
  • Zilin Lan,
  • Haoping Shi,
  • Yinghui Li,
  • Qiang Cheng,
  • Fang Dong,
  • Yingdai Gao,
  • Yao Yao,
  • Tao Cheng,
  • Tuo Wei,
  • Shuquan Rao

摘要

In vivo genetic engineering of haematopoietic stem and progenitor cells (HSPCs) holds the potential to revolutionize the treatment landscape for numerous diseases. However, despite its transformative potential, it remains hindered by the difficulty in efficiently and specifically targeting quiescent human HSCs while maintaining their long-term functionality. Here, after screening 15 lipid nanoparticles (LNPs), we report an LNP that efficiently delivers reporter mRNA to human HSPCs both in ex vivo and in vivo settings when conjugated with the anti-CD34 antibody (CD34/LNPDP). Using CRISPR/Cas editing cargos, CD34/LNPDP achieves high editing efficiency in human HSPCs ex vivo. Intrafemoral administration of CD34/LNPDP in humanized mice results in efficient editing of the erythroid-specific BCL11A enhancer within human HSPCs, enabling the sustained long-term reactivation of fetal haemoglobin (HbF) expression in erythroid cells. In a humanized neutropaenia model harbouring an ELANE mutation, intrafemoral administration of CD34/LNPDP achieves robust editing, targeting exon 2 of ELANE in human HSPCs, partially restoring neutrophil development impairment under long-term observation. Collectively, CD34-targeted delivery enables in vivo HSPC modification without perturbing haematopoiesis, underscoring its suitability for clinical translation.