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.