Cascade-enhanced Pt nanozyme platform anchored on microgels for effective lactate depletion and EndoMT attenuation post-myocardial infarction.

Abstract

Myocardial infarction (MI) often leads to excessive lactate accumulation, which drives endothelial-to-mesenchymal transition (EndoMT) and subsequent myocardial fibrosis. Lactate oxidase (LOx) has been identified as a potential therapeutic enzyme capable of degrading excess lactate. However, the hypoxic environment characteristic of MI diminishes the catalytic efficiency of LOx. In this study, platinum (Pt) nanozymes with catalase-like (CAT-like) activity were introduced, which catalyzed the decomposition of hydrogen peroxide (H₂O₂) to generate oxygen (O₂), thereby enhancing LOx activity. A strategy involving microgel-anchored LOx-loaded Pt nanozymes (PPtL@MGs) was proposed by loading LOx-loaded Pt nanozymes to microgels, enabling targeted delivery and prolonged retention within the infarcted myocardium. The PPtL@MGs exhibited robust CAT-like activity and effectively enhanced LOx-mediated lactate clearance in vitro, thereby alleviating hypoxia/H₂O₂-induced EndoMT in HUVECs. Consequently, it promoted vascular endothelial cadherin (VE-cadherin) expression, suppressed fibroblast-specific protein 1 (FSP1), reduced myocardial fibrosis, and significantly improved cardiac function in vivo. These results demonstrate the potential of this microgel-anchored nanozyme system, which enables cascade-enhanced lactate modulation through O₂ generation and effective lactate clearance, thereby alleviating the MI-induced fibrosis and dysfunction.