Bioinspired nanomedicine for the targeting and treatment of atherosclerosis

As the primary underlying cause of heart attacks and strokes, atherosclerosis places a significant burden on society. Studies over the last decades identified chronic maladaptive inflammation of the vessel wall as a key factor in the disease’s development and progression. Large-scale clinical trials revealed that inhibiting the inflammation that is driving the disease can improve outcomes. However, these trials also highlighted the complications associated with long-term suppression of physiological immune surveillance, which increases the risk of fatal infections and cancer. There is, therefore, an urgent need for therapeutics that can effectively suppress atherosclerosis-driving inflammation, while maintaining the physiological functioning of the immune system. This thesis explores the application of bioinspired nanomedicine to meet this need. We apply two nanomedicine platforms, hyaluronan nanoparticles and HDL nanobiologics, whose designs were inspired by naturally occurring nanomaterials and biological building blocks. This bioinspired approach offers additional benefits by enhancing biocompatibility and exploiting the natural interactions of the materials with their target cells. We explore the mechanisms by which the nanoparticles reach their target cells in the plaque and uncover the crucial role that the endothelium plays in this process. We demonstrate that hyaluronan nanoparticles can be utilized to image vessel wall inflammation, and anti-inflammatory compounds can be incorporated in HDL nanobiologics for treating atherosclerosis. Collectively, the studies in this thesis offer new opportunities for atherosclerosis treatment and identify key mediators of plaque targeting and inflammation.