Matrix metalloproteinase-responsive melanin nanoparticles utilize live neutrophils for targeted high-risk plaque...

Abrupt rupture of atherosclerotic plaque is the predominant contributor to acute cardiovascular events. It is of clinical importance to effectively identify and inhibit high-risk plaque progression. However, this remains a major challenge due to the inadequate targeting of theranostic agents to atherosclerotic lesions. Herein, we utilize live neutrophils to encapsulate melanin-based theranostics (termed MNP_pep-Gd) to enhance their plaque targeting, leveraging the inherent inflammatory tropism of neutrophils in atherosclerosis progression. The MNP_pep-Gd are fabricated using the water-insoluble gadolinium-chelated melanin nanoparticle modified with a detachable polyethylene glycol (PEG) segment via a matrix metalloproteinase (MMP)-cleavable peptide linker. Our work demonstrated that overexpressed MMP in high-risk plaques can induce an increase in particle size and prolonged retention time of the MNP_pep-Gd nanoprobe in lesions, making it a highly efficient contrast agent for magnetic resonance (MR) and photoacoustic (PA) dual-modal imaging atherosclerotic plaque. Concurrently, the melanin nanoparticles function as a therapeutic agent by scavenging multiple toxic reactive oxygen species (ROS), inhibiting the pro-inflammatory cytokines expression, and significantly reducing the foam cell formation. As a result, NE/MNP_pep remarkably alleviates atherosclerosis progression by a 24.7 % reduction for plaque area in ApoE^-/- mice. Immunohistochemical analysis confirmed that NE/MNP_pep treatment significantly reduced the macrophage content by 21.3 % and lipid burden by 15.6 % in plaques. In conclusion, our innovative nanoagent actively targets atherosclerotic sites, offers a noninvasive approach for identifying high-risk atherosclerotic plaques, and significantly contributes to the alleviation of lesion development in ApoE^-/- mice. STATEMENT OF SIGNIFICANCE: Effective identification and inhibition of high-risk plaque progression hold clinical importance. However, it remains a major challenge due to the insufficient targeting of theranostic agents to plaques. Herein, a biomimetic nanoplatform is developed to actively target atherosclerosis plaque with the assistance of neutrophils, thereby minimizing off-target effects. Then, overexpressed MMP2 in high-risk plaques trigger the aggregation of hydrophobic Gd³⁺-labeled melanin nanoparticles, enhancing both MRI/PAI intensities for precise diagnosis. Additionally, the native antioxidant activity of melanin reduces inflammatory level, alleviates oxidative damage, and inhibits plaque progression in ApoE^-/- mice. This study offers valuable insights for accurate plaque assessment and provides effective guidance for subsequent management strategies.