American ginseng-derived extracellular vesicle-like nanoparticles (AGELNs) mitigate doxorubicin-induced cardiotoxicity by inhibiting GPX4-mediated ferroptosis.

Panacis Quinquefolii Radix (American ginseng, AG) has a well-documented history of use in cardiac protection. Nevertheless, the therapeutically active components responsible for its cardioprotective properties have not been fully elucidated. Extracellular vesicle-like nanoparticles (ELNs) have recently emerged as a promising class of natural nanocarriers with diverse applications in medicine and biology. However, it remains uncertain whether American Ginseng-derived extracellular vesicle-like nanoparticles (AGELNs) exhibit cardioprotective effects. This investigation aims to analyze the effects of AGELNs on Doxorubicin-induced cardiotoxicity (DIC) and the mechanisms. Gradient ultracentrifugation was employed to isolate and purify AGELNs, while HPLC was employed for both qualitative and quantitative analysis of saponin molecules in AGELNs. Fluorescently labeled AGELNs were used to assess their uptake in cardiac tissue and cardiomyocytes. DIC models in mice and zebrafish were employed to evaluate the effect of AGELNs against DIC. Transcriptomics, RT-PCR, immunofluorescence, Western blotting, and pharmacological agonist and antagonist treatments were used to elucidate the molecular mechanisms of AGELNs in vivo and in vitro. AGELNs significantly enhanced cardiac function in mice and zebrafish models, evidenced by increased fractional shortening (FS), stroke volume, heart rate, and pericardial sac areas. Concomitantly, AGELNs demonstrated pronounced cardiac accumulation in Dox-treated mice, zebrafish, and cardiomyocytes. Transcriptomic and cellular analyses demonstrated AGELNs attenuate DIC by suppressing lipid peroxidation and ferroptosis. Mechanistically, AGELNs predominantly inhibit cardiomyocyte ferroptosis by targeting GPX4 and activating the NRF2/HO-1/GPX4 pathway. Furthermore, the cardioprotective effect of AGELNs against DIC has been found to be closely linked to its specific combination of bioactive saponins, including Rb1, Rg1, Re, and Rd. AGELNs significantly mitigated DIC by activating GPX4 and suppressing cardiomyocyte ferroptosis in vitro and in vivo. These insights are valuable for the formulation of AGELNs therapies aimed at combating DIC.