Antibody-Conjugated Lipid Nanoparticles Could Enable Targeted Delivery to Long-Term Hematopoietic Stem Cells to Treat Blood Diseases

Abstract

Engineered RNA therapeutics enable modulation of gene expression, while offering a safer alternative to DNA based approaches, however clinical success largely depends on efficient and cell-specific delivery, as naked RNA is unstable in circulation. Lipid nanoparticles (LNPs) have become the leading non-viral vehicle for RNA delivery and have demonstrated clinical efficacy, including the well-known mRNA COVID-19 vaccines developed by Moderna and Pfizer. Although these advances are significant, conventional LNPs primarily localize to the liver after systemic administration, restricting their effectiveness for diseases that require delivery to tissues beyond the liver. Targeting long-term hematopoietic stem cells (LT-HSCs) could enable durable correction of blood disorders such as sickle cell disease, for which existing ex vivo therapies require costly manufacturing and are highly invasive. This work investigates antibody-conjugated LNPs (Ab-LNPs) to target LT-HSC specific surface markers to achieve selective in vivo delivery of gene-editing payloads. Through antibody selection, in vitro screening, in vivo biodistribution, and finally a durability study, this thesis aims to establish a scalable and less invasive gene therapy platform for hematologic diseases.