Bioinspired porous metal-amino acid nanozymes enable multi-pathway treatment of atherosclerosis through anti-oxidation and pro-efferocytosis

Atherosclerosis is characterized by chronic inflammation, persistent oxidative stress, intimal lipid accumulation, and impaired efferocytosis within plaques. Here, we develop a copper-based porous nanozyme assembled through metal-amino acid coordination (MAzyme) for loading an inhibitor of the antiphagocytic CD47-SIRPα signaling pathway and cloaking with macropahge membrane. The resulting biomimetic nanoplatform (MMAzyme-S) inherits both the multi-enzymatic activities of the porous nanozyme and the inflammation-homing features of the biomembranes. The prominent antioxidant effects of MAzyme, comparable to those of natural superoxide dismutase, enable efficient inflammatory resolution via the elimination of reactive oxygen species. Our findings also demonstrate that MMAzyme-S can block CD47-mediated anti-phagocytosis to restore impaired efferocytosis in lesional macrophages, thereby boosting the phagocytic clearance of apoptotic cells. Additionally, cholesterol transport pathways are strengthened through synergistic antioxidant and anti-inflammatory effects, which profoundly reduce foam cell formation and plaque burden. Consequently, with the distinctive advantages of homologous inflammation targeting and multilink intervention in pathogenesis, MMAzyme-S reduces atherosclerotic plaque burden in male ApoE−/− mice. This study highlights the potential of biomimetic porous MAzyme with combined antioxidant and pro-efferocytosis activities as a multifaceted intervention strategy against atherosclerosis. Atherosclerosis is driven by chronic inflammation and persistent oxidative stress accompanied by cholesterol deposition in the intimal layer and impaired efferocytosis within plaques. Here, the authors report a copper-based nanozyme combining plaque-targeting, antioxidant and pro-efferocytosis effects to enable multilink intervention in atherosclerosis pathogenesis and inhibit plaque progression.