Development of a Combined Lipid-Based Nanoparticle Formulation for Enhanced siRNA Delivery to Vascular Endothelial Cells

Pharmaceutics, vol. 14, pp. 2086

Abstract

Low transfection efficiency in endothelial cells (EC) is still a bottleneck for the majority of siRNA-based vascular delivery approaches. In this work, we developed a lipid-based nanoparticle (LNP) formulation based on a combination of a permanently charged cationic lipid-DOTAP and a conditionally ionized cationic lipid-MC3 (DOTAP/MC3) for the enhanced delivery of siRNA into EC. Compared with a single DOTAP or MC3-based benchmark LNP, we demonstrated that the DOTAP/MC3 LNP formulation shows the best transfection efficiency both in primary EC in vitro and in endothelium in zebrafish. The high transfection activity of the DOTAP/MC3 LNP formulation is achieved by a combination of improved endothelial association mediated by DOTAP and MC3-triggered efficient siRNA intracellular release in EC. Furthermore, AbVCAM-1-coupled DOTAP/MC3 LNP-mediated siRNARelA transfection showed pronounced anti-inflammatory effects in inflammatory-activated primary EC by effectively blocking the NF-κB pathway. In conclusion, the combination of permanent and ionizable cationic lipids in LNP formulation provides an effective endothelial cell delivery of siRNA.

Authors 6

1. Yutong He

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Medical Biology Section, Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands

2. Dongdong Bi Aachen Division of BioTherapeutics Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2300 RA Leiden, The Netherlands

3. Josée A. Plantinga

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Medical Biology Section, Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands

4. Grietje Molema

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Medical Biology Section, Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands

5. Jeroen Bussmann Aachen Division of BioTherapeutics Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2300 RA Leiden, The Netherlands

6. Jan A. A. M. Kamps corresponding

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Medical Biology Section, Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands