A Scalable, Antibody-Free Lipid Nanoparticle Achieves Preferential mRNA Delivery to Human HSPCs In Vivo Without Conditioning.

Authors

Eunyoung Kim, Ryan Zenhausern, Shivani Kapadia, Sylvanie Johnson, Skylar Cho, Joanne Choi, Kernyu Park, Edgard Diaz, Ananda R Podilapu, Ramachandran Kuppan, James E Dahlman, Hyejin Kim, Janghee Woo

Published in

Molecular therapy : the journal of the American Society of Gene Therapy. Oct 23, 2026. Epub Oct 23, 2026.

Abstract

Systemic nucleic acid delivery to hematopoietic stem and progenitor cells (HSPCs) remains a major barrier to in vivo gene therapy due to hepatic sequestration of lipid nanoparticles (LNPs). Here, we report a scalable, ligand-free HSPC-tropic LNP enabling efficient mRNA delivery to human HSPCs in vivo without conditioning. In humanized NBSGW mice, the LNP preferentially delivered mRNA to human HSPCs and early myeloid progenitors, with limited delivery to lymphoid and non-hematopoietic cells. Single-cell transcriptomic and multiomic analyses revealed no broad transcriptional perturbation associated with delivery. Compared with the SM-102 LNP, the HSPC-tropic LNP achieved greater mRNA delivery to human HSPCs, while exhibiting substantially reduced hepatic delivery. The LNP also enabled functional delivery of Cas9 mRNA and β2M-targeting sgRNA to human CD34⁺ HSPCs, resulting in efficient gene editing and reduced β2M expression. These findings establish a ligand-free platform for functional RNA delivery and genome engineering in human HSPCs.

PMID:
42920299
Bibliographic data and abstract were imported from PubMed on 24 Oct 2026.

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