A neutrophil-mimetic nanoplatform integrating lipid mediators and immunoregulation for myocardial repair

Myocardial infarction (MI) triggers excessive oxidative stress and uncontrolled inflammation, which impede cardiac repair. Conventional anti-inflammatory or antioxidant therapies often fail to restore immune homeostasis or promote tissue regeneration effectively. Hence, developing a multifunctional strategy that concurrently modulates lipid mediators, scavenges reactive oxygen species (ROS), and reprograms immune responses is crucial for achieving coordinated myocardial healing. We designed a neutrophil-mimetic nanoplatform that integrates the lipid mediators resolvin D1 (RvD1) and α-linolenic acid (ALA) within a bioinspired neutrophil membrane (NM) coating. This multifunctional system harnesses the natural homing ability of neutrophil membranes, endogenous antioxidant activity, and dual lipid mediator delivery. A combination of in vitro hypoxia/reoxygenation (H/R) assays, macrophage polarization studies, and in vivo MI rat models was employed to evaluate its antioxidative, anti-inflammatory, and reparative performance. NM@NP@ALA@RvD1 exhibited efficient ROS scavenging, inhibited neutrophil overactivation, and promoted macrophage polarization toward a pro-resolving phenotype. The nanoplatform sustained PPARγ activation and restored redox and immune balance in ischemic myocardium, leading to reduced infarct size, suppressed fibrosis, and improved cardiac function. Transcriptomic analysis confirmed coordinated regulation of oxidative stress and inflammation-related pathways. This study establishes a bioinspired, lipid-mediator-driven nanoplatform that harmonizes oxidative and immune responses in myocardial repair. By integrating neutrophil biomimicry, lipid mediator signaling, and antioxidant defense, NM@NP@ALA@RvD1 offers a potential paradigm for precise, multi-mechanistic cardioprotective therapy.