Angelica sinensis Polysaccharide nanoparticles can improve myocardial ischemia-reperfusion injury by inhibiting ferritinophagy via the ATF6/NCOA4 pathway

Background Ferroptosis aggravates myocardial ischemia-reperfusion injury (MI/RI) by disrupting iron homeostasis, accelerating lipid peroxidation, and elevating reactive oxygen species (ROS) levels. Although Angelica sinensis polysaccharide (ASP) has shown protective effects against MI/RI, its clinical translation remains limited due to poor bioavailability and low target specificity. Methods To address these limitations, we developed ASP@PLGA-PEG nanoparticles using a solvent evaporation method and characterized their morphology, size distribution, and surface charge by transmission electron microscopy, dynamic light scattering, and zeta potential analysis. The protective effects of ASP@PLGA-PEG were evaluated in vitro using HL-1 cardiomyocytes subjected to oxygen and glucose deprivation/reoxygenation (OGD/R). Cell viability, mitochondrial membrane potential, ROS generation, lipid peroxidation, and antioxidant capacity were assessed using CCK-8 assay, JC-1 staining, ROS fluorescence detection, immunofluorescence, and biochemical analyses. In addition, an in vitro MI/RI model was established using the Langendorff isolated heart perfusion system to assess hemodynamic function, infarct size, histopathological changes, and mitochondrial ultrastructure. Results ASP@PLGA-PEG nanoparticles significantly reduced oxidative stress, improved cardiomyocyte viability, and inhibited ferroptosis in OGD/R-injured HL-1 cells. In the Langendorff model, treatment with ASP@PLGA-PEG effectively decreased myocardial infarct size, preserved cardiac hemodynamics, and alleviated structural damage. Mechanistic studies revealed that ASP@PLGA-PEG nanoparticles activate ATF6 signaling, which suppresses NCOA4-mediated ferritinophagy, thereby limiting iron overload and lipid peroxidation to protect cardiomyocytes against ferroptosis during MI/RI. Conclusions This study demonstrates that ASP@PLGA-PEG nanoparticles exert potent cardioprotective effects through a multi-target mechanism involving ER stress modulation, enhanced antioxidative defense, and inhibition of ferritinophagy-driven ferroptosis. These findings highlight the therapeutic potential of ASP@PLGA-PEG as a promising nanomedicine strategy for the prevention and treatment of myocardial ischemia-reperfusion injury.