Increased Bone Marrow Uptake and Accumulation of Very-Late Antigen-4 Targeted Lipid Nanoparticles

Lipid nanoparticles (LNPs) have evolved rapidly as promising delivery systems for oligonucleotides, including siRNAs. However, current clinical LNP formulations show high liver accumulation after systemic administration, which is unfavorable for the treatment of extrahepatic diseases, such as hematological disorders. Here we describe the specific targeting of LNPs to hematopoietic progenitor cells in the bone marrow. Functionalization of the LNPs with a modified Leu-Asp-Val tripeptide, a specific ligand for the very-late antigen 4 resulted in an improved uptake and functional siRNA delivery in patient-derived leukemia cells when compared to their non-targeted counterparts. Moreover, surface-modified LNPs displayed significantly improved bone-marrow accumulation and retention. These were associated with increased LNP uptake by immature hematopoietic progenitor cells, also suggesting similarly improved uptake by leukemic stem cells. In summary, we describe an LNP formulation that successfully targets the bone marrow including leukemic stem cells. Our results thereby support the further development of LNPs for targeted therapeutic interventions for leukemia and other hematological disorders.

Automated summary

Lipid nanoparticles (LNPs) are rapidly evolving as promising delivery systems for oligonucleotides, including siRNAs. In this study, LNPs were specifically targeted to hematopoietic progenitor cells in the bone marrow using a modified tripeptide ligand. Functionalized LNPs showed improved uptake and delivery of siRNA in patient-derived leukemia cells, as well as increased accumulation and retention in the bone marrow. These findings suggest the potential of LNPs for targeted therapy in leukemia and other hematological disorders.