Delivery of plant-derived sbi-miR5564a via exosome-like nanovesicles protects against ionizing radiation-induced oxidative damage

Coix seed seedlings-derived exosome-like nanovesicles (CSSELNs) have demonstrated significant potential in alleviating ionizing radiation (IR)-induced damage. However, the role of bioactive substances, particularly whether microRNAs (miRNAs) significantly contribute to their radioprotective effects, remains unclear. In this study, we identified miRNAs enriched in CSSELNs by small RNA sequencing, followed by validation of the key miRNAs. It was found that sbi-miR5564a confers protection against IR-induced oxidative stress in THLE-2 cells. Bioinformatics analysis together with cell-based and animal experiments were conducted to explore their potential mechanism. The results indicated that sbi-miR5564a, when delivered through CSSELNs, targeted and downregulated EP300, thereby modulating the JNK/FOXO3a signaling pathway, leading to the restoration of reactive oxygen species to normal levels and protection against IR-induced damage. Notably, a single oral dose of sbi-miR5564a@CSSELNs, which were highly enriched with sbi-miR5564a, exerted highly effective protective effects in vivo, comparable to that achieved by 30-day oral gavage of CSSELNs alone. This study not only clarified the radioprotective effect of sbi-miR5564a but also established CSSELNs as a natural miRNA delivery platform. This advancement promotes the application of plant-derived nanovesicles in radioprotective effects and the development of functional foods.