Targeting Ligand Independent Tropism of siRNA‐LNP by Small Molecules for Directed Therapy of Liver or Myeloid Immune Cells

Hepatic clearance of lipid nanoparticles (LNP) with encapsulated nucleic acids restricts their therapeutic applicability. Therefore, tools for regulating hepatic clearance are of high interest for nucleic acid delivery. To this end, this work employs wild‐type (WT) and low‐density lipoprotein receptor (Ldlr)−/− mice pretreated with either a leukotriene B4 receptor inhibitor (BLT1i) or a high‐density lipoprotein receptor inhibitor (HDLRi) prior to the injection of siRNA‐LNP. This work is able to demonstrate significantly increased hepatic uptake of siRNA‐LNP by the BLT1i in Ldlr−/− mice by in vivo imaging and discover an induction of specific uptake‐related proteins. Irrespective of the inhibitors and Ldlr deficiency, the siRNA‐LNP induced RNA‐binding and transport‐related proteins in liver, including haptoglobin (HP) that is also identified as most upregulated serum protein. This work observes a downregulation of proteins functioning in hepatic detoxification and of serum opsonins. Most strikingly, the HDLRi reduces hepatic uptake and increases siRNA accumulation in spleen and myeloid immune cells of blood and liver. RNA sequencing demonstrates leukocyte recruitment by the siRNA‐LNP and the HDLRi through induction of chemokine ligands in liver tissue. The data provide insights into key mechanisms of siRNA‐LNP biodistribution and indicate that the HDLRi has potential for extrahepatic and leukocyte targeting. Using a small‐molecule based inhibitor specific for an immune cell specific receptor, Lin and colleagues increase targeting of siRNA‐LNP (lipid nanoparticles) to their default target cell hepatocytes. By inhibition of hepatocyte‐specific high‐density lipoprotein receptor (HDLR), the LNP accumulation gets extrahepatic and shifts toward immune cells. The beauty is that existing LNP formulations and approved inhibitors might be used for targeted therapies without the need for targeting ligands.