Liver-targeted siRNA delivery via artificial red blood cells to lower LDL-C
Mei Feng1, Shiqi Tang1, Yuyan Qin1
1The Fifth Affiliated Hospital, The Affiliated Panyu Central Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
Abstract:
Elevated levels of low-density lipoprotein cholesterol (LDL-C) are a key risk factor contributing to the progression of ischemic heart disease. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) with small interfering RNA (siRNA) provides an alternative therapeutic option for lowering LDL-C levels. However, the poor pharmacokinetic profiles of naked siRNA hinder clinical application. Herein, we present a siRNA delivery system based on polyamidoamine nanoparticles with galactose-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-modified red blood cell membrane (GRMPS). GRMPS achieved targeted delivery of PCSK9 siRNA to hepatocytes and accumulation of siRNA in the liver for efficient down-regulation of PCSK9 expression and inhibition of LDL receptor, eventually lowering plasma LDL-C level without inducing obvious toxicity. This strategy developed a potential platform for delivering siRNA agents to treat various liver disorders.
Insights
This study introduces a novel nanoparticle system for targeted delivery of proprotein convertase subtilisin/kexin type 9 (PCSK9) small interfering RNA (siRNA). This approach effectively lowers low-density lipoprotein cholesterol (LDL-C) levels, offering a promising therapeutic strategy.
Area of Science:
- Biomedical Engineering
- Molecular Biology
- Cardiovascular Research
Background:
- Elevated low-density lipoprotein cholesterol (LDL-C) is a primary driver of ischemic heart disease progression.
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition using small interfering RNA (siRNA) presents a therapeutic avenue for LDL-C reduction.
- Limitations in naked siRNA pharmacokinetics impede its clinical use.
Purpose of the Study:
- To develop an effective siRNA delivery system for targeted hepatic delivery and PCSK9 inhibition.
- To evaluate the efficacy and safety of a novel nanoparticle-based siRNA delivery platform for lowering LDL-C.
Main Methods:
- Development of a red blood cell membrane-camouflaged nanoparticle (GRMPS) for siRNA delivery.
- In vivo administration of GRMPS loaded with PCSK9 siRNA in a relevant model.
- Assessment of PCSK9 expression, LDL receptor levels, plasma LDL-C, and toxicity.
Main Results:
- GRMPS facilitated targeted delivery and liver accumulation of PCSK9 siRNA.
- Efficient down-regulation of PCSK9 expression and inhibition of LDL receptor were observed.
- Significant reduction in plasma LDL-C levels was achieved without apparent toxicity.
Conclusions:
- The GRMPS system demonstrates a viable strategy for targeted siRNA delivery to hepatocytes.
- This platform shows potential for treating hypercholesterolemia and other liver-related disorders.
- The developed nanoparticle system offers a promising therapeutic platform for siRNA-based interventions.
