Extracellular vesicles, mitochondria-derived vesicles and exosomal miRNA (exomiR) signaling in cancer: phytochemical targeting of a novel chemopreventive frontier

Cancer remains one of the leading causes of mortality worldwide, with its progression intimately linked to complex intercellular communication networks within the tumor microenvironment. Exosomes are nanoscale extracellular vesicles (EVs) of endosomal origin acting as active mediators of intercellular communication. Importantly, exosomes have emerged as critical mediators of intracellular communication that can influence microenvironmental homeostasis by transferring their bioactive cargo including proteins, lipids, and nucleic acids between cells. Although exosomes are the best-characterized miRNA carriers, other EV subclasses, including plasma membrane-derived microvesicles, apoptotic bodies, large oncosomes and migrasomes, also convey miRNAs and modify recipient cell behavior, and are therefore considered here alongside exosomes. We further examine mitochondria-derived vesicles (MDVs), a distinct vesicular pathway that connects mitochondrial quality control to the endosomal compartment and that may act upstream of exosomal miRNA loading. Among their cargo, exosome-derived microRNAs (exomiRs) have attracted considerable attention for their ability to negatively regulate gene expression in recipient cells, modulating key oncogenic processes such as angiogenesis, invasion, immune evasion, epithelial-to-mesenchymal transition, drug resistance, and cancer-related stem cell activity. This review aims to synthesize current knowledge on the biogenesis and function of EVs, including exosomes and MDVs, and of exomiRs linked with carcinogenesis and specifically addresses emerging evidence supporting pharmacological and nutraceutical interventions to modulate exomiR profiles as a novel chemopreventive strategy. We further discuss how diet-derived nutraceuticals, including plant polyphenols and isoflavones, can alter the microRNA expression landscape in cancer cells and their secreted exosomes, and we provide a global, cross-study overview of the miRNAs reported to respond to phytochemical exposure. In addition, we discuss the potential consequences of these modulations in several key carcinogenesis-associated processes such as angiogenesis, inflammation, oxidative stress, and stem cell mobilization. While direct targeting of exomiRs remains technically challenging, recent reports support the hypothesis that intracellular miRNA modulation may propagate to the exosomal compartment, thereby influencing intercellular communication. Collectively, this evidence highlights microRNA modulation as an indirect yet promising strategy to influence exosome-mediated intercellular communication in cancer and provides a conceptual framework for understanding exomiRs as a programmable layer of tumor-associated signaling. MicroRNA modulation by nutraceuticals and drugs may extend to the exosomal compartment. Exosome-associated miRNAs (exomiRs) are proposed as a dynamic interface of intercellular signaling. Emerging evidence suggests that intracellular microRNA levels alter the exosomal cargo composition, and that EV subclasses other than exosomes also convey miRNAs. Mitochondria-derived vesicles (MDVs) and mitochondrial stress may act as upstream regulators of exosomal signaling. Modulating miRNAs affects multiple signaling pathways that, in turn, indirectly reshape tumor microenvironment communication.