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.

Polarization of tumor associated macrophages (TAMs) has been a promising therapeutic paradigm for tumor. However, how to achieve precise regulation of TAMs and high efficiency of tumor immunotherapy is still a huge challenge. Here, we report dicarboxy fullerene modified with mannose (DCFM) as an immunomodulator to selectively polarize TAMs and prominently boost anti-tumor immunity. The dicarboxy fullerene molecule was synthesized through the Prato reaction and further covalently bonded with mannose, obtaining the DCFM with well-defined structure. Due to the exist of mannose in DCFM, it could accurately recognize mannose receptor in TAMs. Our cellular experiment results showed that mannose modification could notably promote the uptake of DCFM by the immunosuppressive M2-type macrophages that effectively reprogrammed M2-type macrophages into anti-tumor M1-type macrophages, leading to enhance the phagocytosis of tumor cells by macrophages and inhibiting tumor cells migration. Subsequently, we observed that DCFM could significantly distribute into tumor tissues by in vivo fluorescence imaging. Importantly, DCFM exhibited a superior anti-tumor efficiency in the subcutaneous colorectal tumor model. In addition, it showed that DCFM precisely polarized TAMs into M1-type macrophages and actively increased the infiltration of cytotoxic T lymphocytes (CTLs), inducing profound tumor growth inhibition.