The hidden bioactive molecules: miRNAs loaded in extracellular vesicles might act as bioactive constituents in European mistletoe

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Herbal products are globally accepted as a valid complementary system of therapy in the form of pharmaceuticals or food supplements. Often their bioactive constituents and corresponding interactions with human have not been comprehensively characterized. Various studies around the world have been initiated to develop scientific evidence-based herbal therapies. New plant bioactive molecules are being discovered. MicroRNAs (miRNAs) are a class of approximately 22 nucleotides single-stranded non-coding RNAs that play crucial roles in gene expression. Recently, the cross-kingdom of plant derived miRNAs has attracted great attraction. For example, the rice miRNAs have been suggested to enter mammalian bloodstream and have a functional role in mammalian metabolism. Plant-derived miR159 can target human genes and suppress breast cancer cell growth in vitro and in vivo. These studies suggested that human genes can be regulated by dietary plant miRNAs, providing thrilling clues that medicinal plants miRNAs might be the hidden bioactive compounds regulating human health and diseases. Mistletoe (Viscum album L.) has been used traditionally in Europe for centuries for the treatment of cancer and cardiovascular diseases but their scientific background is still controversially discussed. By using high-throughput Illumina sequencing and bioinformatics analysis, our previous study indicated that mistletoe miRNAs might be involved in the pharmacological effects of mistletoe. Further experimental validations are currently urgent to confirm the bioactivities of these plant miRNAs. Considering plant miRNAs are not stable in enzymatic environment such as herb extracts and mammalian body fluids, being encapsulated into extracellular vesicles (EVs) that are membrane-enclosed nano-sized particles released by cells, could offer miRNAs nano-shuttles allowing them to travel long distances. Herein, we propose that mistletoe miRNAs might serve as an independent category of active ingredients and might be responsible for or at least contribute to the pharmacological effects (e.g. anti-tumor effect) of mistletoe. Mistletoe EVs might act as effective vehicles to deliver miRNAs with intact functionality, and mediate the cross-kingdom regulation of mistletoe miRNAs. Proposed investigations will be focused on the profiling of cross-kingdom regulatory miRNAs, identification of mammalian targets and visualization of mistletoe EVs mediated miRNA delivery. If our hypothesis is proven, it will promote our understanding of miRNA-based bioactive ingredients in medicinal plants provide scientific support for folk medicinal use and clinical use of medicinal plants. More importantly, it will open new ways for the development of miRNA-based therapies to prevent or treat human diseases.