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

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 lipopolysaccharide-stimulated 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-1 beta, interleukin-6, and tumor necrosis factor-alpha). 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 Gd3+-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.