Engineering nanomaterials to address cell-mediated inflammation in atherosclerosis

Abstract

Atherosclerosis is an inflammatory disorder with a pathophysiology driven by both innate and adaptive immunity and a primary cause of cardiovascular disease (CVD) worldwide. Vascular inflammation and accumulation of foam cells and their products induce maturation of atheromas, or plaques, which can rupture by metalloprotease action, leading to ischemic stroke or myocardial infarction. Diverse immune cell populations participate in all stages of plaque maturation, many of which directly influence plaque stability and rupture via inflammatory mechanisms. Current clinical treatments for atherosclerosis focus on lowering serum levels of low-density lipoprotein (LDL) using therapeutics such as statins, administration of antithrombotic drugs, and surgical intervention. Strategies that address cell-mediated inflammation are lacking, and consequently have recently become an area of considerable research focus. Nanomaterials have emerged as highly advantageous tools for these studies, as they can be engineered to target specific inflammatory cell populations, deliver therapeutics of wide-ranging solubilities and enhance analytical methods that include imaging and proteomics. Furthermore, the highly phagocytic nature of antigen presenting cells (APCs), a diverse cell population central to the initiation of immune responses and inflammation, make them particularly amenable to targeting and modulation by nanoscale particulates. Nanomaterials have therefore become essential components of vaccine formulations and treatments for inflammation-driven pathologies like autoimmunity, and present novel opportunities for immunotherapeutic treatments of CVD. Here, we review recent progress in the design and use of nanomaterials for therapeutic assessment and treatment of atherosclerosis. We will focus on promising new approaches that utilize nanomaterials for cell-specific imaging, gene therapy and immunomodulation.

Figure 1. Comparison of subcutaneous and intravenous routes of administration for nanomaterial-based treatment of atherosclerotic lesions

Choice in route of administration may alter nanomaterial biodistribution and the resulting immunomodulation. Subcutaneous injection is most likely to target nanomaterials to nearby lymph nodes, where they are internalized and processed by antigen presenting cells (APCs). These cells may then activate other immune cells, promoting their trafficking to the atheroma and/or secretion of cytokines that can elicit systemic pro- or anti-inflammatory responses. Intravenous injection is more likely to result in targeting of the atheroma directly for local imaging or modulation of inflammation, but the majority of nanomaterials may be lost to phagocytic cell populations within the major organs of the mononuclear phagocyte system (MPS): the liver, spleen, and kidneys. As a secondary lymphoid organ, the spleen is a major site of nanomaterial uptake and processing by APCs. These splenocytes may activate other immune cells and/or secrete cytokines systemically, both of which can alter atheroma development and progression remotely.

Figure 2

Size, shape, charge, and surface chemistry are important variables to consider when designing nanomaterials for the modulation of inflammatory cells.