Targeting macrophages with multifunctional nanoparticles to detect and prevent atherosclerotic cardiovascular disease

Abstract

Despite the emergence of novel diagnostic, pharmacological, interventional, and prevention strategies, atherosclerotic cardiovascular disease remains a significant cause of morbidity and mortality. Nanoparticle (NP)-based platforms encompass diverse imaging, delivery, and pharmacological properties that provide novel opportunities for refining diagnostic and therapeutic interventions for atherosclerosis at the cellular and molecular levels. Macrophages play a critical role in atherosclerosis and therefore represent an important disease-related diagnostic and therapeutic target, especially given their inherent ability for passive and active NP uptake. In this review, we discuss an array of inorganic, carbon-based, and lipid-based NPs that provide magnetic, radiographic, and fluorescent imaging capabilities for a range of highly promising research and clinical applications in atherosclerosis. We discuss the design of NPs that target a range of macrophage-related functions such as lipoprotein oxidation, cholesterol efflux, vascular inflammation, and defective efferocytosis. We also provide examples of NP systems that were developed for other pathologies such as cancer and highlight their potential for repurposing in cardiovascular disease. Finally, we discuss the current state of play and the future of theranostic NPs. Whilst this is not without its challenges, the array of multifunctional capabilities that are possible in NP design ensures they will be part of the next frontier of exciting new therapies that simultaneously improve the accuracy of plaque diagnosis and more effectively reduce atherosclerosis with limited side effects.

Keywords: Atherosclerosis; Macrophages; Nanoparticles.

Graphical Abstract

Figure 1

Initiation and progression of atherosclerosis—highlighting the role and origins of plaque macrophages. Atherosclerosis is initiated when LDL infiltrates into the subendothelial space where it undergoes oxidation to form oxLDL. Circulating bone marrow-derived monocytes are attracted to the site of oxLDL deposition by the activated endothelium releasing pro-inflammatory cytokines, attaching to the endothelial surface by adhesion molecules (ICAM/VCAM) and migrate across the endothelium. Within the intima, monocytes differentiate into macrophages to engulf the trapped oxLDL, leading to foam cell formation. Other potential sources of plaque macrophages include the trans-differentiation of SMCs to macrophage-like cells and additionally tissue-resident macrophages. Medial SMCs also migrate into the intima releasing collagen which contributes to the formation of the fibrous cap overlying the plaque. Once macrophages are unable to process the cholesterol from engulfed lipoproteins, they undergo apoptosis contributing to the formation of the necrotic core. Continued release of pro-inflammatory cytokines leads to further immune cell recruitment and infiltration, exacerbating atherosclerosis progression. This highlights the major contribution of plaque macrophages to atherosclerosis initiation and progression as well as the sources of these macrophages. LDL, low-density lipoprotein; oxLDL, oxidized LDL; VCAM1, vascular cell adhesion molecule-1; ICAM1, intercellular adhesion molecule-1; BM, bone marrow. Figure created with BioRender.com.

Figure 2

Using NPs to therapeutically target macrophages in atherosclerosis. Theranostic NPs typically consist of imaging/sensing and therapeutic components incorporated into a NP carrier. These NPs may also contain a ligand for targeting plaque macrophages and can therapeutically modulate a variety of pro-atherosclerotic mechanisms. Some of these NPs have utilized various therapeutic strategies to modulate the metabolism of low-density lipoprotein (LDL), such as decreasing monocyte recruitment via CCR2 inhibition using siRNA. These NPs prevent the accumulation of inflammatory cells and reduce LDL oxidation (oxLDL), which inhibits oxLDL uptake by macrophages. Molecular inhibition of mediators, such as TRAF6, also reduces macrophage accumulation. In addition, light-induced therapies such as photodynamic therapy (PDT) and photothermal therapy (PTT) can be used to cause macrophage ablation. Others have also attempted to restore defective efferocytosis to promote removal of apoptotic debris from the plaque. Promoting cholesterol efflux from plaque using high-density lipoprotein (HDL)-like NPs is another therapeutic strategy to decrease foam cell formation.

Figure 3

Macrophage functions targeted by NPs that reduce atherosclerosis. Theranostic NPs have been designed to target a host of macrophage functions and elicit beneficial effects including: (i) anti-inflammatory effects using statin release from statin-HDL (sHDL) and cargo-switching NPs (CSNPs) as well via antagonism of CCR2 using a peptide in a peptide-conjugated NP (CCTV) and through liposome-based NPs loaded with anti-inflammatory prednisolone phosphate (L-PLPs); (ii) inhibiting the uptake of oxidized LDL (ox-LDL) using biomimetic NPs that release their payload when they come in contact with ROS and also through direct inhibition of the scavenger receptor CD36 using sugar-derived amphophilic macromolecule NPs (SDAMNPs) that release anti-oxidant α-tocopherol upon interaction with CD36; (iii) enhancing cholesterol efflux using NPs that activate LXR which increases the expression of the cholesterol transporters ABCA1 and ABCG1, and porphysomes that efflux cholesterol via the scavenger receptor SR-B1; (iv) restoring defective efferocytosis using SWNT that inhibit CD47 and through NPs that cause siRNA-mediated inhibition of Ca2+/calmodulin-dependent kinase γ (siCAMk2 g NPs); and (v) finally, through inhibition of monocyte activation using a small molecule inhibitor of TNF receptor-associated factor 6 (TRAF6) loaded inside HDL-like NPs (TRAF6i-rHDL).