The role of lipids in exosome biology and intercellular communication: Function, analytics and applications.

Exosomes are extracellular vesicles that in recent years have received special attention for their regulatory functions in numerous biological processes. Recent evidence suggests a correlation between the composition of exosomes in body fluids and the progression of some disorders, such as cancer, diabetes and neurodegenerative diseases. In consequence, numerous studies have been performed to evaluate the composition of these vesicles, aiming to develop new biomarkers for diagnosis and to find novel therapeutic targets. On their part, lipids represent one of the most important components of exosomes, with important structural and regulatory functions during exosome biogenesis, release, targeting and cellular uptake. Therefore, exosome lipidomics has emerged as an innovative discipline for the discovery of novel lipid species with biomedical applications. This review summarizes the current knowledge about exosome lipids and their roles in exosome biology and intercellular communication. Furthermore, it presents the state-of-the-art analytical procedures used in exosome lipidomics while emphasizing how this emerging discipline is providing new insights for future applications of exosome lipids in biomedicine.

State-of-the-art exosome loading and functionalization techniques for enhanced therapeutics: a review.

Exosomes are a subpopulation of cell membrane-derived vesicles which play an essential role in cellular communication. In recent years, several studies have exploited the natural properties of exosomes as nanocarriers for several applications such as immunotherapy or drug delivery. Consequently, numerous techniques have been developed to improve their immunogenicity, drug loading efficiency, or targeting. Nonetheless, to date, there is no consensus on which technique results in more advantages for this purpose. In this context, this review discusses the currently used methodologies regarding traditional and engineered exosome loading and targeting techniques. Here, we focus on the advantages and disadvantages of each method while discussing some results obtained in relevant reports. Although there is a lack of evidence regarding the effects of exogenous exosomes in humans and several limitations in exosome isolation and purification techniques at the large-scale exist, the formulation of new exosome-based therapeutics is in the spotlight. Therefore, the development of more efficient functionalization techniques is required to reduce the potential risks associated with the clinical use of these vesicles.

Electrokinetically Driven Exosome Separation and Concentration Using Dielectrophoretic-Enhanced PDMS-Based Microfluidics.

Exosomes are a specific subpopulation of extracellular vesicles that have gained interest because of their many potential biomedical applications. However, exosome isolation and characterization are the first steps toward designing novel applications. This work presents a direct current-insulator-based dielectrophoretic (DC-iDEP) approach to simultaneously capture and separate exosomes by size. To do so, a microdevice consisting of a channel with two electrically insulating post sections was designed. Each section was tailored to generate different nonuniform spatial distributions of the electric field and, therefore, different dielectrophoretic forces acting on exosomes suspended in solution. Side channels were placed adjacent to each section to allow sample recovery. By applying an electric potential difference of 2000 V across the length of the main channel, dielectrophoretic size-based separation of exosomes was observed in the device. Analysis of particle size in each recovered fraction served to assess exosome separation efficiency. These findings show that iDEP can represent a first step toward designing a high-throughput, fast, and robust microdevice capable of capturing and discriminating different subpopulations of exosomes based on their size.

Recent advances and challenges in the recovery and purification of cellular exosomes.

Exosomes are nanovesicles secreted by most cellular types that carry important biochemical compounds throughout the body with different purposes, playing a preponderant role in cellular communication. Because of their structure, physicochemical properties and stability, recent studies are focusing in their use as nanocarriers for different therapeutic compounds for the treatment of different diseases ranging from cancer to Parkinson's disease. However, current bioseparation protocols and methodologies are selected based on the final exosome application or intended use and present both advantages and disadvantages when compared among them. In this context, this review aims to present the most important technologies available for exosome isolation while discussing their advantages and disadvantages and the possibilities of being combined with other strategies. This is critical since the development of novel exosome-based therapeutic strategies will be constrained to the effectiveness and yield of the selected downstream purification methodologies for which a thorough understanding of the available technological resources is needed.

Removal and biotransformation of 4-nonylphenol by Arthrospira maxima and Chlorella vulgaris consortium.

4-Nonylphenol (4-NP) is an anthropogenic contaminant found in different environmental matrices that has an effect over the biotic and abiotic factors within the environment. Bioremediation by microorganisms can be used as a potential treatment to remove this pollutant. In this work, a consortium of two microorganisms, Arthrospira maxima and Chlorella vulgaris, was employed to remove 4-NP from water. The parameters analyzed included cell growth, removal of 4-NP, and 4-NP remnant in the biomass. In addition, the metabolites produced in the process by this consortium were identified. It was found that C. vulgaris is more resistant to 4-NP than A. maxima (cell growth inhibition by 4-NP of 99%). The consortium used in this study had an IC50 greater than any strain of microalgae or cyanobacteria reported for 4-NP removal (9.29 mg/L) and reduced up to 96% of 4-NP in water in the first 48 h of culture. It was also observed that there is a bio-transformation of 4-NP, comparable with the process carried out by another bacterium, in which three similar metabolites were found (4-(1-methyl-octyl)-4-hydroxy-cyclohex-2-enone, 4-nonyl-4-hydroxy-ciclohexa-2,5-dienone and 4-nonyl-4-hydroxy- ciclohex-2-enone) and one that is similar to plant metabolism (4-nonyl-(1-methyl,6,8-metoxy)-hydroxybenzene). These results indicate that microalgae and cyanobacteria consortium can be used to remove 4-NP from water.

Clinical Implications of Exosomal PD-L1 in Cancer Immunotherapy.

Inhibiting the programmed cell death ligand-1 (PD-L1)/programmed cell death receptor-1 (PD-1) signaling axis reinvigorates the antitumor immune response with remarkable clinical efficacy. Yet, low response rates limit the benefits of immunotherapy to a minority of patients. Recent studies have explored the importance of PD-L1 as a transmembrane protein in exosomes and have revealed exosomal PD-L1 as a mechanism of tumor immune escape and immunotherapy resistance. Exosomal PD-L1 suppresses T cell effector function, induces systemic immunosuppression, and transfers functional PD-L1 across the tumor microenvironment (TME). Because of its significant contribution to immune escape, exosomal PD-L1 has been proposed as a biomarker to predict immunotherapy response and to assess therapeutic efficacy. In this review, we summarize the immunological mechanisms of exosomal PD-L1, focusing on the factors that lead to exosome biogenesis and release. Next, we review the effect of exosomal PD-L1 on T cell function and its role across the TME. In addition, we discuss the latest findings on the use of exosomal PD-L1 as a biomarker for cancer immunotherapy. Throughout this review, we propose exosomal PD-L1 as a critical mediator of tumor progression and highlight the clinical implications that follow for immuno-oncology, discussing the potential to target exosomes to advance cancer treatment.

Potential Applications and Functional Roles of Exosomes in Cardiometabolic Disease.

Despite diagnostic and therapeutic advances, cardiometabolic disease remains the leading cause of death worldwide. Extracellular vesicles (EVs), which include exosomes and microvesicles, have gained particular interest because of their role in metabolic homeostasis and cardiovascular physiology. Indeed, EVs are recognized as critical mediators of intercellular communication in the cardiovascular system. Exosomes are naturally occurring nanocarriers that transfer biological information in the setting of metabolic abnormalities and cardiac dysfunction. The study of these EVs can increase our knowledge on the pathophysiological mechanisms of metabolic disorders and their cardiovascular complications. Because of their inherent properties and composition, exosomes have been proposed as diagnostic and prognostic biomarkers and therapeutics for specific targeting and drug delivery. Emerging fields of study explore the use exosomes as tools for gene therapy and as a cell-free alternative for regenerative medicine. Furthermore, innovative biomaterials can incorporate exosomes to enhance tissue regeneration and engineering. In this work, we summarize the most recent knowledge on the role of exosomes in cardiometabolic pathophysiology while highlighting their potential therapeutic applications.