Gastrodia elata Blume-derived exosomes-like nanovesicles deliver miR-221-3p and miR-222-3p to ameliorate doxorubicin cardiotoxicity

BACKGROUND AND PURPOSE The widely used antitumor drug doxorubicin (DOX) is clinically limited because of its tendency to induce cardiotoxicity, and there is currently no optimal protection strategy. Plant-derived exosomes-like nanovesicles have shown potential for treating a variety of diseases. Here, we report the therapeutic effects of Gastrodia elata Blume-derived exosomes-like nanovesicles (GE-ELNs) in mitigating DOX cardiotoxicity and explore the underlying mechanisms. METHODS AND RESULTS GE-ELNs exhibited a typical morphology and size consistent with mammalian exosomes and were enriched in RNA, proteins, and lipids. In vivo IVIS imaging confirmed the recruitment of GE-ELNs to the heart after intravenous injection. Fluorescence microcopy and flow cytometry analysis revealed a time and dose-dependent increase in the uptake of GE-ELNs by cardiomyocytes. While GE-ELNs treatment decreased apoptosis and restored calcium transients in DOX-treated cardiomyocytes, it did not significantly affect the toxicity of DOX in several breast cancer cell lines. In a rat model of acute DOX cardiotoxicity, GE-ELNs mitigated cardiotoxicity and improved left ventricular function and cardiac structure. Similar protective effects were also observed in BALB/c mice with implanted breast cancer xenografts without promoting tumor growth or metastasis or comprising the antitumor efficiency of DOX. Mechanistic studies using RNA sequencing and miRNA mimics/inhibitor transfection revealed that miR-221-3p and miR-222-3p are key factors that mediate the protective effects of GE-ELNs. CONCLUSIONS Collectively, our study revealed that while GE-ELNs attenuated DOX cardiotoxicity, they had very limited effects on the survival of cancer cells and tumor growth. GE-ELNs may represent a novel therapeutic approach to prevent DOX cardiotoxicity.