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.

Atherosclerosis (AS) is a condition associated with dysfunctional lipid metabolism and an inflammatory immune microenvironment that remains the leading cause of severe cardiovascular events. Drugs exhibiting both anti-inflammatory and lipid-scavenging...