Recently, exosomes secreted by menstrual mesenchymal stem cells have been identified as inhibitory agents of tumor angiogenesis and modulators of the tumor cell secretome in prostate and breast cancer. However, their direct effect on endothelial cells and paracrine mediators have not yet been investigated. Using a carrier-based cell culture system to test the scalability for exosome production, we showed that different types of endothelial cells present specific kinetics for exosomes internalization. Exosome-treatment of endothelial cells increased cytotoxicity and reduced VEGF secretion and angiogenesis in a dose-dependent manner. Using the hamster buccal pouch carcinoma as a preclinical model for human oral squamous cell carcinoma, we demonstrated a significant antitumor effect of intra-tumoral injection of exosomes associated with a loss of tumor vasculature. These results address up-scaling of exosome production, a relevant issue for their clinical application, and also assess menstrual stem cell exosomes as potential anti-angiogenic agents for the treatment of neoplastic conditions.

Hypoxia‐inducible factor 1 α (HIF1α), a regulator of metabolic change, is required for the survival and differentiation potential of mesenchymal stem/stromal cells (MSC). Its role in MSC immunoregulatory activity, however, has not been completely elucidated. In the present study, we evaluate the role of HIF1α on MSC immunosuppressive potential. We show that HIF1α silencing in MSC decreases their inhibitory potential on Th1 and Th17 cell generation and limits their capacity to generate regulatory T cells. This reduced immunosuppressive potential of MSC is associated with a metabolic switch from glycolysis to OXPHOS and a reduced capacity to express or produce some immunosuppressive mediators including Intercellular Adhesion Molecule (ICAM), IL‐6, and nitric oxide (NO). Moreover, using the Delayed‐Type Hypersensitivity murine model (DTH), we confirm, in vivo, the critical role of HIF1α on MSC immunosuppressive effect. Indeed, we show that HIF1α silencing impairs MSC capacity to reduce inflammation and inhibit the generation of pro‐inflammatory T cells. This study reveals the pivotal role of HIF1α on MSC immunosuppressive activity through the regulation of their metabolic status and identifies HIF1α as a novel mediator of MSC immunotherapeutic potential.

Here, we successfully present a novel, cost, and time-saving method to generate sEV from encapsulated MSCs. Future applications include using encapsulated cells as a retrievable delivery device that can interact with the host niche by releasing active agents in vivo, including sEV, growth factors, hormones, and small molecules, while avoiding cell clearance, and the negative side-effect of releasing undesired components including apoptotic bodies. Finally, particles produced following the encapsulation protocol display beneficial features for their use as drug-loaded delivery vehicles.

Small extracellular vesicles (sEVs) have burst into biomedicine as a natural therapeutic alternative for different diseases. Considered nanocarriers of biological origin, various studies have demonstrated the feasibility of their systemic administration, even with repeated doses. However, despite being the preferred route of physicians and patients, little is known about the clinical use of sEVs in oral administration. Different reports show that sEVs can resist the degradative conditions of the gastrointestinal tract after oral administration, accumulating regionally in the intestine, where they are absorbed for systemic biodistribution. Notably, observations demonstrate the efficacy of using sEVs as a nanocarrier system for a therapeutic payload to obtain a desired biological (therapeutic) effect. From another perspective, the information to date indicates that food-derived vesicles (FDVs) could be considered future nutraceutical agents since they contain or even overexpress different nutritional compounds of the foods from which they are derived, with potential effects on human health. In this review, we present and critically analyze the current information on the pharmacokinetics and safety profile of sEVs when administered orally. We also address the molecular and cellular mechanisms that promote intestinal absorption and that command the therapeutic effects that have been observed. Finally, we analyze the potential nutraceutical impact that FDVs would have on human health and how their oral use could be an emerging strategy to balance nutrition in people.