Abstract
Low-density lipoprotein cholesterol (LDL-C) is usually considered as a "bad cholesterol" for it is one of the major risk factors for coronary heart disease. As a scavenger of LDL-C, the low density lipoprotein receptor (LDLR) binds with LDL-C in the liver. However, the protein levels and function of LDLR are regulated by Proprotein convertase subtilisin/kexin type 9 (PCSK9). Loss of PCSK9 induces the increase of LDLR levels and reduction of plasma LDL-C. Here, we developed a novel style of artificial platelets with biomimetic properties, high stability, and long circulation which enabled the efficient delivery of siRNA targeting Pcsk9. The bioinspired nanoparticles induced Pcsk9 mRNA reduction by 66% in vitro. For in vivo studies, the nanoparticles accumulated in the liver to reduce Pcsk9 transcription, which results in ∼28% reduction in plasma LDL-C concentrations with negligible effects on either high density lipoprotein cholesterol (HDL-C) or triglycerides (TGs). These results demonstrated the use of artificial platelets to deliver siRNA and induce effective RNAi therapeutics to specifically lower LDL-C which provides a potential strategy to lower PCSK9 and treat hypercholesterolemia.
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