Lipid Nanoparticles for Nucleic Acid Delivery to Endothelial Cells

Abstract

Endothelial cells play critical roles in circulatory homeostasis and are also the gateway to the major organs of the body. Dysfunction, injury, and gene expression profiles of these cells can cause, or are caused by, prevalent chronic diseases such as diabetes, cardiovascular disease, and cancer. Modulation of gene expression within endothelial cells could therefore be therapeutically strategic in treating longstanding disease challenges. Lipid nanoparticles (LNP) have emerged as potent, scalable, and tunable carrier systems for delivering nucleic acids, making them attractive vehicles for gene delivery to endothelial cells. Here, we discuss the functions of endothelial cells and highlight some receptors that are upregulated during health and disease. Examples and applications of DNA, mRNA, circRNA, saRNA, siRNA, shRNA, miRNA, and ASO delivery to endothelial cells and their targets are reviewed, as well as LNP composition and morphology, formulation strategies, target proteins, and biomechanical factors that modulate endothelial cell targeting. Finally, we discuss FDA-approved LNPs as well as LNPs that have been tested in clinical trials and their challenges, and provide some perspectives as to how to surmount those challenges.

Keywords: endothelial cells; gene delivery; lipid nanoparticle; nanoparticles; nucleic acids.

Fig. 1

Endothelial cells in healthy and diseased environments. (A) Endothelial cells line the inner surface of blood vessels, controlling blood clotting, vessel size, immune function, and the passage of cells or molecules out of the circulation. By producing anticoagulant proteins such as thrombomodulin, TFPI, and EPCR, endothelial cells prevent clot formation inside blood vessels to enable proper oxygen and nutrient delivery to vascularized tissues in the body [–6]. Endothelial cells also sense blood fluidity and produce gasses such as nitric oxide and hydrogen sulfide to regulate vascular flow [12, 19, 51]. Additionally, because endothelial cells are in direct contact with numerous blood components such as protein, sugars, and lipids, endothelial cells serve as a gateway for molecules to travel in-and-out of the circulation. CD36, transferrin, and insulin receptors along with caveolae on endothelial cells allow the passage of selective molecules out of the circulation, while fenestrations on endothelial cells enable the passage of low molecular weight solutes across the endothelium [–28]. (B) When endothelial cells become dysfunctional, numerous physiological functions become altered, resulting in cardiovascular dysfunction that could lead to serious medical complications. For example, decreased production of anticoagulant proteins by endothelial cells could promote blood clots to form inside of blood vessels, altering blood fluidity and potentially inducing thrombosis [, –54]. Decreased production of nitric oxide or hydrogen sulfide leads to inflammation and increases in blood pressure, conditions that could lead to atherosclerosis if they become chronic [, , –57]. Systemic overexpression of adhesion molecules associated with inflammation, including P-selectin, E-selectin, ICAM-1, and VCAM-1, on endothelial cells can cause cardiac dysfunction [–61].