A new technology for delivering nucleic acid therapeutics—such as small interfering RNA (siRNA), antisense oligonucleotides (ASOs), and messenger RNA (mRNA)—to bone marrow cells appears to overcome long-posed challenges of stability and precision targeting. Dutch researchers from the Eindhoven University of Technology and Radboud University Medical Center developed a breakthrough nanotechnology platform that exploits natural lipoprotein trafficking mechanisms to overcome delivery barriers and enable gene silencing, expression, or editing in vivo. The apolipoprotein nanoparticles (aNPs) showcased the safe and targeted delivery of nucleic acids to hematopoietic stem and progenitor populations. This study, published in Nature Nanotechnology, paves the way for developing therapeutics with diverse applications such as immunoregulation, vaccination, and gene editing for hereditary diseases, all with high biocompatibility and the potential for repeated dosing.
Expanding beyond LNP delivery
The success of genetic drugs relies on delivery technologies that protect nucleic acids from degradation while ensuring targeted delivery to specific cells. Lipid nanoparticle (LNP) technology has enabled groundbreaking advancements, including the first siRNA therapeutic for hereditary transthyretin amyloidosis and COVID-19 mRNA vaccines. Efforts to expand LNP delivery beyond the liver include incorporating charged phospholipids, antibody modifications, and DNA barcoding. However, further development of biocompatible, tunable platforms is essential to fully realizing the systemic potential of RNA therapeutics.
This study introduces a nanotechnology platform leveraging natural lipoproteins for targeted delivery of nucleic acid therapeutics to bone marrow myeloid cells and hematopoietic progenitors. The researchers—co-led by Stijn R. J. Hofstraat, Tom Anbergen, and Robby Zwolsman—developed a novel two-step flow manufacturing process to produce aNPs capable of delivering siRNA. The prototype aNP consists of DMPC, cholesterol, tricaprylin (forming the core matrix for siRNA), the ionizable lipid MC3, and apolipoprotein A1 (ApoA1). The prototype formulation demonstrated over 80% efficiency in siRNA recovery, entrapment, and retention, highlighting its robust incorporation capabilities. To optimize the platform, researchers created a library of 72 aNP formulations by varying the key components, whittled down to 30 promising aNP candidates, with eight representative formulations chosen for in vivo testing.
Target RNA delivery to bone marrow
The researchers identified the formulation that exhibited the most consistent and broad gene-silencing capability across hematopoietic stem and progenitor populations, which was selected for further development and testing. The researchers tracked the biodistribution of the aNP-siRNA in mice, finding significant accumulation in the bone marrow and spleen, with no signs of toxicity in the liver or kidneys.
In a tumor model, the aNP-siRNA demonstrated safe, targeted immune modulation in cancer therapy (albeit in reducing an immunosuppressive response and not an anti-cancer response). These results contrasted with a clinically approved MC3-based LNP formulation, which failed to achieve significant silencing. Additionally, the platform proved effective for splice-switching with ASO and mRNA-based protein production, showcasing its promise for expanding the applications of RNA therapeutics beyond the liver.
These findings highlight the platform’s versatility and translational promise, offering a new avenue for delivering gene therapies to myeloid cells and hematopoietic progenitors with precision and stability. With the potential to deliver siRNA, ASOs, and mRNA, aNPs are well-suited for therapeutic immunoregulation, vaccination, and gene editing for hereditary diseases. The platform’s high biocompatibility, repeat dosing potential, modularity, and scalability make it a promising candidate for clinical applications.