Plasma free fatty acids levels are increased in subjects with obesity and type 2 diabetes, playing detrimental roles in the pathogenesis of atherosclerosis and cardiovascular diseases. Increasing evidence showing that dysfunction of the vascular endothelium, the inner lining of the blood vessels, is the key player in the pathogenesis of atherosclerosis. In this review, we aimed to summarize the roles and the underlying mechanisms using the evidence collected from clinical and experimental studies about free fatty acid-mediated endothelial dysfunction. Because of the multifaceted roles of plasma free fatty acids in mediating endothelial dysfunction, elevated free fatty acid level is now considered as an important link in the onset of endothelial dysfunction due to metabolic syndromes such as diabetes and obesity. Free fatty acid-mediated endothelial dysfunction involves several mechanisms including impaired insulin signaling and nitric oxide production, oxidative stress, inflammation and the activation of the renin-angiotensin system and apoptosis in the endothelial cells. Therefore, targeting the signaling pathways involved in free fatty acid-induced endothelial dysfunction could serve as a preventive approach to protect against the occurrence of endothelial dysfunction and the subsequent complications such as atherosclerosis.

Cancer is a deadly disease that is globally and consistently one of the leading causes of mortality every year. Despite the availability of chemotherapy, radiotherapy, immunotherapy, and surgery, a cure for cancer has not been attained. Recently, exosomes have gained significant attention due to the therapeutic potential of their various components including proteins, lipids, nucleic acids, miRNAs, and lncRNAs. Exosomes constitute a set of tiny extracellular vesicles with an approximate diameter of 30–100 nm. They are released from different cells and are present in biofluids including blood, cerebrospinal fluid (CSF), and urine. They perform crucial multifaceted functions in the malignant progression of cancer via autocrine, paracrine, and endocrine communications. The ability of exosomes to carry different cargoes including drug and molecular information to recipient cells make them a novel tool for cancer therapeutics. In this review, we discuss the major components of exosomes and their role in cancer progression. We also review important literature about the potential role of exosomes as vaccines and delivery carriers in the context of cancer therapeutics.

Background: Malignant glioma is a fatal brain cancer. Accumulated evidence has demonstrated that exosomes can cross the blood–brain barrier (BBB), suggesting their potential use as drug delivery vehicles to glioma. Therefore, various loading methods of anticancer agents into exosomes have been developed. However, the loading efficiency of anticancer drugs, such as doxorubicin (DOX) and paclitaxel (PTX), into exosomes is relatively low, thus challenging to improve the drug delivery efficiency to glioma cells (GMs) via exosomes. Methods: To improve the loading efficiency of doxorubicin into exosomes, a microfluidic device (Exo-Load) was developed. Next, to increase the exosomal delivery of doxorubicin to GMs, autologous exosomes were used for its loading via Exo-Load. Briefly, exosomes from SF7761 stem cells-like- and U251-GMs were isolated and characterized by nano-tracking analysis (NTA), transmission electron microscopy (TEM), and immunogold EM. Finally, doxorubicin was successfully loaded into exosomes with saponin by Exo-Load, and the uptake and functionality of doxorubicin-loaded exosomes for parent GMs were evaluated. Results: The loading efficiency of DOX into SF7761 stem cells-like- and U251-GMs-derived-exosomes were 19.7% and 7.86% via Exo-Load at the injection flow rate of 50 μL/min, respectively. Interestingly, the loading efficiency of DOX into U251 GMs-derived exosomes was significantly improved to 31.98% by a sigmoid type of Exo-Load at the injection flow rate of 12.5 μL/min. Importantly, DOX-loaded GMs-derived exosomes via Exo-Load inhibited parent GMs’ proliferation more than heterologous GMs, supporting exosomes’ homing effect. Conclusion: This study revealed that DOX and PTX could be loaded in exosomes via Exo-Load, demonstrating that Exo-Load could be a potential drug-loading device into exosomes with further optimization. This study also demonstrated that the delivery of DOX to SF7761 GMs via their daughter exosomes was much more efficient rather than U251 GMs-derived exosomes, supporting that the use of autologous exosomes could be better for glioma drug targeting.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the predominant impairment of neurons in the hippocampus and the formation of amyloid plaques, hyperphosphorylated tau protein, and neurofibrillary tangles in the brain. The overexpression of amyloid-β precursor protein (APP) in an AD brain results in the binding of APP intracellular domain (AICD) to Fe65 protein via the C-terminal Fe65-PTB2 interaction, which then triggers the secretion of amyloid-β and the consequent pathogenesis of AD. Apparently, targeting the interaction between APP and Fe65 can offer a promising therapeutic approach for AD. Recently, exosome, a type of extracellular vesicle with diameter around 30–200 nm, has gained much attention as a potential delivery tool for brain diseases, including AD, due to their ability to cross the blood–brain barrier, their efficient uptake by autologous cells, and their ability to be surface-modified with target-specific receptor ligands. Here, the engineering of hippocampus neuron cell-derived exosomes to overexpress Fe65, enabled the development of a novel exosome-based targeted drug delivery system, which carried Corynoxine-B (Cory-B, an autophagy inducer) to the APP overexpressed-neuron cells in the brain of AD mice. The Fe65-engineered HT22 hippocampus neuron cell-derived exosomes (Fe65-EXO) loaded with Cory-B (Fe65-EXO-Cory-B) hijacked the signaling and blocked the natural interaction between Fe65 and APP, enabling APP-targeted delivery of Cory-B. Notably, Fe65-EXO-Cory-B induced autophagy in APP-expressing neuronal cells, leading to amelioration of the cognitive decline and pathogenesis in AD mice, demonstrating the potential of Fe65-EXO-Cory-B as an effective therapeutic intervention for AD.

Noninvasive detection of exosomal MCT1/CD147 can monitor the progression of glioma, a fatal brain tumor, as a liquid biopsy.