Fat-Based Drug Delivery Targets Hidden Cause of Heart Disease: New Treatment for Atherosclerosis

As a disease in which fat-like materials accumulate in the arteries resulting in inflammation and blood vessel constriction, atherosclerosis may cause heart attacks and strokes. Although scientists have long recognized that the immune system is involved in this disease, its specific role has been uncertain.

In a new study, by the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) in Spain, it was found that conventional type 1 dendritic cells (cDC1s) can exacerbate atherosclerosis. The findings, which were published in Circulation Research, also provided a possible new method of treating the disease by targeting these cells.

Dendritic cells, as part of  the immune system, assist in identifying infections or threats and stimulating T cells, which destroy disease-causing invaders. DCs are divided into subtypes, such as cDC1s and cDC2s. Conventional type 1 DC1s have been characterized by their effector function to activate CD8+ T cells and induce a robust inflammatory environment through the secretion of a chemical signal, interferon-y (IFN-y).

Previous studies provided inconclusive evidence regarding the contribution of cDC1s to atherosclerosis. Results of some studies that implied cDC1s could offer protection against the disease and some that implied they could worsen it. The researchers at CNIC used Ldlr−/− mice prone to atherosclerosis development and conducted experiments in which cDC1s were increased or eliminated to find a more definitive answer.

In one experiment, the researchers used the FLT3L gene to increase cDC1s in mice. These mice were given a high-cholesterol diet for 8 weeks, and they had bigger and more inflamed plaques that formed in their arteries. In a another experiment, the team depleted cDC1s in the mice. Even when these mice were given the same diet, they formed smaller plaques and had reduced inflammation. Regression of plaques was attributed to the decrease in the number of inflammatory T cells (CD4+ Th1 and CD8+ IFN-γ + cells) in the arteries.

The researchers also discovered that the detrimental actions of cDC1s were connected to a molecule within them known as STING (stimulator of interferon genes). STING aids the cells to generate inflammation. The disease-promoting effects were diminished when they blocked STING in cDC1s.

On the basis of these results, the researchers designed a novel therapy based on small fat-based structures known as lipid nanoparticles. These were crafted to deliver an anti-inflammatory drug, dexamethasone, specifically to cDC1s. The nanoparticles were coated with an antibody that binds specifically to a marker present on cDC1s known as CLEC9A.

In mice with atherosclerosis, these  nanoparticles reduced atheroma plaque formation and decreased inflammation when tested and did so without compromising the antiviral fighting capabilities of the mice, which is typically an adverse effect of immune system–suppressing treatments.

The study demonstrates that cDC1s have a detrimental effect in atherosclerosis and provides the possibility of treating the disease through direct targeting of these cells.