Natural Cell Patches: Melanin Nanoparticles for MR Imaging‐Guided Antiatherosclerosis Therapy via Attenuating Macrophage Pyroptosis

Abstract

Pyroptosis, characterized by inflammasome activation, membrane Gasdermin D (GSDMD)-pore formulation, and the rapid release of inflammatory cytokines, can induce plaque instability and atherosclerosis progression. Nevertheless, insights into the precise antiatherosclerosis therapies targeting pyroptosis remain limited. Here, a novel biomedical application of natural polyphenol melanin as a theranostic antipyroptosis defense nanoplatform for atherosclerosis is reported. Ultrasmall melanin nanoparticles are easily fabricated and functionalized with cyclo-Arg-Gly-Asp-d-Tyr-Lys conjugated polyethylene glycol to yield cRGD-PEG-MNPs (RpMPs) to target plaque neovascularization, which is confirmed by fluorescence imaging. Importantly, RpMPs act like cell patches to suppress pyroptosis in lipopolysaccharidestimulated macrophages by scavenging reactive oxygen species, downregulating the expression levels of pyroptosis-related proteins (NLRP3, Caspase 1, and GSDMD) and reducing the leakage of inflammatory cytokines (interleukin-1β, interleukin-6, and tumor necrosis factor-α). In vivo studies further reveal that RpMPs can ameliorate the development and improve the stability of atherosclerotic plaques via attenuating NLRP3-stimulated pyroptosis and inducing an anti-inflammatory phenotype in the aorta of ApoE −/− mice. Moreover, chelator-free Gd 3+ -RpMPs exhibit persistent T 1 -weighted contrast-enhanced efficiency and plaque resident on a 9.4 T Micro magnetic resonance scanner in murine atherosclerosis model. Overall, this study suggests the potential for using melanin to develop natural multifunctional nanoplatforms for molecular theranostic in atherosclerosis and other pyroptosis-related diseases.

Engineering Nanoplatforms for Theranostics of Atherosclerotic Plaques

“…[234][235][236][237][238] For instance, Zhang et al developed ultrasmall melanin nanoparticles called RpMPs that were functionalized with cRGD peptide to achieve ROS elimination at a molecular level for the treatment of atherosclerotic plaques (Figure 10E). [239] The administration of RpMPs resulted in downregulation of pyroptosis-associated phenotypes and reduced expression of inflammatory cytokines, effectively eliminating ROS within plaque macrophages and inhibiting pyroptosis. The RpMPs-treated group exhibited a higher fluorescence intensity in plaque-bearing aortas compared to the control group, indicating excellent targeting efficiency of RpMPs toward atherosclerotic lesions (Figure 10F).…”

Nanomaterials for Disease Treatment by Modulating the Pyroptosis Pathway

“…[ 170 ] Zhang et al reported an anti‐pyroptosis defense nanoplatform that inhibits pyroptosis by scavenging ROS to improve the progression of atherosclerosis. [ 171 ] The preparation of these nanomaterials has created a new way of thinking about the treatment of diseases and a possibility for the future clinical treatment of pyroptosis‐related diseases.…”

Reactive Oxygen Species-Responsive Sequentially Targeted AIE Fluorescent Probe for Precisely Identifying the Atherosclerotic Plaques

“…4,5 Meanwhile, macrophages play a critical role in uptaking the oxidized low density lipoprotein (ox-LDL) to deteriorate into the foam cells, simultaneously releasing various inflammatory factors and then inducing the formation of atherosclerotic plaque. 6,7 Clinical study has found that the foam cell-rich atherosclerotic plaque is prone to rupture into thrombus, inducing some fatal complications such as myocardial infarction and stroke. 8,9 Thence, it is highly important to efficiently recognize the foam cells and then precisely identify the morphology and disperse distribution of the plaques for physicians to make timely clinical decisions and perform proactive interventions as early as possible.…”

“…10 Currently, computed tomography (CT), 11 optical coherence tomography (OCT), 12 magnetic resonance imaging (MRI), 13 and ultrasonography (US) 14 are utilized to detect the structural and anatomic features of atherosclerotic plaques. 6 However, these conventional methods always have difficulty in providing the detailed information for atherosclerotic lesions owing to their intrinsically low spatial resolution. 15 Fluorescence imaging has become as an indispensable modality because of its high sensitivity, excellent spatial resolution, and fast acquisition and image processing.…”

“…Cardiovascular diseases (CVDs) are the leading cause of global mortality and disability, accounting for almost half of total death annually. − Atherosclerosis (AS) is an inflammation-driven chronic disease caused by the asymptomatic buildup of plaques on the arterial wall to the formation of atherosclerotic plaque, even the rupture of plaque. , Meanwhile, macrophages play a critical role in uptaking the oxidized low density lipoprotein (ox-LDL) to deteriorate into the foam cells, simultaneously releasing various inflammatory factors and then inducing the formation of atherosclerotic plaque. , Clinical study has found that the foam cell-rich atherosclerotic plaque is prone to rupture into thrombus, inducing some fatal complications such as myocardial infarction and stroke. , Thence, it is highly important to efficiently recognize the foam cells and then precisely identify the morphology and disperse distribution of the plaques for physicians to make timely clinical decisions and perform proactive interventions as early as possible …”