Artificial Platelets for Efficient siRNA Delivery to Clear "Bad Cholesterol"

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 similar to 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.

低密度脂蛋白胆固醇（LDL - C）通常被视为“坏胆固醇”，因为它是冠心病的主要危险因素之一。作为LDL - C的清道夫，低密度脂蛋白受体（LDLR）在肝脏中与LDL - C结合。然而，LDLR的蛋白水平和功能受前蛋白转化酶枯草杆菌蛋白酶/可馨型9（PCSK9）调节。PCSK9缺失会导致LDLR水平升高以及血浆LDL - C降低。在此，我们开发了一种新型的具有仿生特性、高稳定性和长循环的人工血小板，它能够高效递送靶向Pcsk9的小干扰RNA（siRNA）。这种仿生纳米颗粒在体外使Pcsk9 mRNA降低66%。在体内研究中，纳米颗粒在肝脏中聚集以减少Pcsk9转录，这使得血浆LDL - C浓度降低约28%，而对高密度脂蛋白胆固醇（HDL - C）或甘油三酯（TGs）的影响可忽略不计。这些结果证明了利用人工血小板递送siRNA并诱导有效的RNA干扰疗法以特异性降低LDL - C，这为降低PCSK9和治疗高胆固醇血症提供了一种潜在策略。