Exosomes as a New Class of Cell-Free Therapeutics and Diagnostics

Exosomes are extracellular vesicles (EVs) of endosomal origin that range in size between 30 and 150 nanometers (nm). Exosomes are formed by the invagination of the cell membrane. This invagination and subsequent budding result in the formation of early endosomes. These early endosomes then mature into late endosomes, which are also called multivesicular bodies (MVBs). Finally, these MVBs migrate and fuse with the plasma membrane to release exosomes outside the cell.

Exosome uptake can then be performed neighboring cells or by cells at distant sites that were travelled to via the bloodstream. In either case, exosomes get into other cells by fusion or ligand-receptor interactions.

Exosomes as Cell-to-Cell Communication

Today, exosomes are thought to be a means of cell-to-cell communication and intercellular macromolecular transport. They have also been found to play an important role in the transmission of proteins, lipids, mRNAs, miRNAs, and DNA, and to be the cause of many diseases. This particular feature of exosomes can be exploited by using them as natural carriers of drug payloads.

Exosomes are secreted by a wide range of cells and the contents carried by them depend strongly on their cell of origin. Virtually all living cells that have been studied show exosome-mediated communication. The exosomal contents of cells can include proteins such as enzymes, as well as mRNAs and ncRNAs, lipids, and other types of cargo.

The contents of the exosomes can serve as useful cancer biomarkers or as biomarkers for other indications, such as neurodegenerative diseases. Such uses have compelled a rapid rise in exosome-mediated cancer biomarker research, including the use of exosomes for the detection, monitoring, and treatment of a diverse range of oncologic conditions.

Use of Exosomes as Biomarkers

The major reason for the focus on the use of exosomes as biomarkers is that they are present in nearly all biofluids, including serum, plasma, urine, seminal fluid, CSF, saliva, tears and breast milk. This makes exosome diagnostics practical because of their ease of use, speed of detection, and minimally invasive nature. Exosomes can also act as overall prognostic indicators and predictors of response to treatment.

As mentioned, exosomes carry cell-specific cargos of proteins, lipids, and nucleic acids that are selectively taken up by recipient cells. While exosomes are secreted by all the different types of cells, their cargos are different from each other. Thus, exosomal cargo can offer prognostic information for a range of diseases, such as inflammation, cardiovascular, renal, neurodegenerative, metabolic and cancer.

One of the main mechanisms by which exosomes are thought to exert their effects is via the transfer of exosome-associated RNA to recipient cells, where they influence protein machinery. For example, miRNAs and lncRNAs are shuttled by exosomes and can alter gene expression, while proteins (e.g. heat shock proteins, cytoskeletal proteins, adhesion molecules, membrane transporter and fusion proteins) can directly affect target cells.

Researchers investigating biomarkers in exosomes have discovered, identified, and reported the presence of hundreds of biomolecules present in the lumen of exosomes. Understandably, there is an urgent need to identify exosomal markers for characterization of exosomes, particularly exosomes originating from cancer cells.

Exosomes as “Mini Versions” of Parental Cells

Today, exosomes are often regarded as “mini versions” of their parental cell. This is because they are complex in architecture with specially sorted proteins, lipids, nucleic acids, and other content that is highly dependent on their cell type of origin.

Commonly, exosomes are enriched in proteins with various functions, such as:

• Tetraspanins (CD9, CD63, CD81, CD82), which take part in cell penetration, invasion, and fusion events
• Heat shock proteins (HSP70, HSP90), as part of the stress response that are involved in antigen binding and presentation
• MVB formation proteins that are involved in exosome release (Alix, TSG101)
• Proteins responsible for membrane transport and fusion (annexins and Rab)

The Rise of Exosome Therapeutics

Notwithstanding the advantages of some cell-based therapies, many challenges remain. The challenges associated with cell-based therapies include clinical risks such as inflammation, the possibility of a potent immune response, potential viral contamination, manufacturing costs, and regulatory issues. Thus, some cell-therapy developers are now seeking alternative therapies with similar outcomes but fewer risks and challenges. One of these potential alternatives is exosome therapeutics.

Companies participating in exosome sector are of two types: companies using “naïve” exosomes and companies using “engineered” exosomes. Naïve exosomes are the exosomes naturally released by cells, while “engineered” exosomes are those loaded with additional biomolecules in the laboratory.

At this time:

• Avalon, Aegle Therapeutics, ExoCoBio, Capricor, AgeX Therapeutics, and United Therapeutics are examples of companies focusing on “naïve” exosomes.
• Exopharm and Avalon are involved with both types of exosomes.
• Codiak, Evox, Ilias, Carmine Therapeutics, Aruna Bio, ReNeuron, Anjarium, Adipomics, Brainstorm Cell Therapeutics, Exocure Biosciences, and TriArm Therapeutics are dealing with “engineered” exosomes.

What are your thoughts on the rise of exosomes as cell-free therapeutics and diagnostics? Share them in the comments below.

To learn more about this rapidly evolving field, view the “Global Exosome Market – Market Size, Forecast, Trials and Trends, 2022.”