PEG-modified fullerene nanoparticles attenuate myocardial injury via dual modulation of inflammatory response and endothelial barrier restoration

Abstract Intimate immune hyperactivation and subsequent vascular endothelial dysfunction are involved in the main pathophysiology of heart failure (HF). However, existing treatments through immunomodulation and endothelial protection for HF are not fully developed. In this study, we introduced PEGylated C60 fullerene nanoparticles (FNPs-PEG2000, FPs) as a two-pronged strategy to mitigate myocardial injury in mice with HF via superior immunomodulation combined with endothelial barrier restoration. The FPs exhibit prolonged systemic circulation, potent reactive oxygen species (ROS) scavenging capacity, and biocompatibility. Mechanistically, FPs suppress M1-type macrophage polarization, inhibit macrophage pyroptosis via the caspase-1/GSDMD pathway blockade, and restore endothelial barrier integrity by stabilizing junctional proteins. In a murine post-infarction HF model, FPs significantly improve cardiac function (left ventricular ejection fraction: 34.1% vs. 19.2% in HF controls), reduce fibrosis, and normalize pathological markers. Single-cell transcriptomics further reveal FPs-driven immunomodulation (66.48% neutrophil reduction and 78.98% endothelial restoration) and pro-angiogenic gene activation. Collectively, FPs demonstrate a multimodal therapeutic mechanism by disrupting ROS-inflammation crosstalk, preserving endothelial barrier integrity, and promoting cardiac repair, thus offering a promising translational candidate for HF management.