Development of a Combined Lipid-Based Nanoparticle Formulation for Enhanced siRNA Delivery to Vascular Endothelial Cells
Yutong He,
Dongdong Bi,
Josée A. Plantinga,
Grietje Molema,
Jeroen Bussmann,
Jan A. A. M. Kamps
Affiliations
Yutong He
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
Dongdong Bi
Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2300 RA Leiden, The Netherlands
Josée A. Plantinga
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
Grietje Molema
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
Jeroen Bussmann
Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, 2300 RA Leiden, The Netherlands
Jan A. A. M. Kamps
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
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.
