Designed fat-based particles for long-lasting editing of blood stem cells inside human-like mice

An LNP conjugated with an anti-CD34 antibody enables efficient delivery of CRISPR/Cas editing cargos to human hematopoietic stem and progenitor cells.

• The identified lipid nanoparticle (CD34/LNP^DP) effectively delivers reporter mRNA to human HSPCs in both ex vivo and in vivo settings.
• High editing efficiency of the erythroid-specific BCL11A enhancer is achieved in human HSPCs using CD34/LNP^DP.
• Sustained long-term reactivation of fetal hemoglobin (HbF) expression in erythroid cells is enabled following intrafemoral administration of CD34/LNP^DP in humanized mice.
• In a humanized neutropenia model with an ELANE mutation, CD34/LNP^DP robustly edits exon 2 of ELANE in human HSPCs.
• This editing partially restores neutrophil development impairment over long-term observation.
• CD34-targeted delivery facilitates in vivo modification of HSPCs without disrupting normal blood cell production.

Simplified