A nature-inspired nanodelivery platform for gene silencing in hematopoietic stem and progenitor cells

Abstract Nucleic acid therapeutics harbor great potential for silencing, expressing, or editing genes. Here, we introduce a nanodelivery platform based on natural lipoproteins, which prevents premature degradation of small interfering RNA (siRNA), ensuring its targeted and intracellular delivery to hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. After establishing a prototype apolipoprotein lipid nanoparticle (aNP) that stably incorporates siRNA in its core, we built a comprehensive library of which we thoroughly characterized the individual aNPs’ physicochemical properties. Following the in vitro screening of all formulations, we selected eight siRNA-aNPs that are representative of the library’s diversity, and determined their capacity to silence lysosomal-associated membrane protein 1 (LAMP1) in immune cell subsets in mice, using an intravenous administration regimen. Our data show that using different aNPs, we can achieve functional gene silencing in immune cell subsets and their bone marrow progenitors. Beyond gene silencing, the aNP platform’s inherent capacity to engage immune cells provides it with considerable potential to deliver other types of nucleic acid therapeutics to HSPCs.