Neutrophil-tropic APL@Mn3O4 nanozymes alleviate myocardial ischemia-reperfusion injury through redox regulation

Myocardial ischemia-reperfusion injury (MIRI) is driven by coupled oxidative and inflammatory amplification after reperfusion, with activated neutrophils acting as early upstream effectors that propagate secondary cardiomyocyte injury. Strategies limited to downstream oxidative damage may therefore be insufficient to interrupt this reinforcing cascade. We developed an agglutinated-protein liposome formulation encapsulating Mn 3 O 4 nanozymes (APL@Mn 3 O 4 ), designed to integrate delivery directed toward activated neutrophils with catalytic redox regulation. The agglutinated-protein liposomal surface supported complement-associated tropism toward activated neutrophils under inflammatory conditions, whereas the Mn 3 O 4 core retained catalytic antioxidant activity for reactive oxygen species (ROS) regulation. In vitro , APL@Mn 3 O 4 reduced neutrophil oxidative and inflammatory responses without measurably impairing migratory capacity under the tested conditions. In a neutrophil-cardiomyocyte co-culture system, APL@Mn 3 O 4 attenuated oxidative stress and apoptosis in injured cardiomyocytes. In vivo , APL@Mn 3 O 4 preferentially associated with circulating neutrophils, attenuated oxidative and inflammatory myocardial injury, and improved post-reperfusion cardiac remodeling and function. These findings support APL@Mn 3 O 4 as a neutrophil-tropic nanozyme platform for alleviating MIRI by attenuating pathological neutrophil-associated oxidative and inflammatory activity and reducing secondary cardiomyocyte injury.