Articles by AGS
Microalgae Extracellular Vesicles (MEV), a New Delivery System, May be the Key to Opening Oral Administration to the Intestine, the GALT and the Spleen.

AGS is developing microalgae extracellular vesicles (MEVs), a universal drug delivery system, for oral administration of biologics (peptides, proteins, DNAs, RNAs). Produced by Chlorella, a single cell microalgae, MEVs are natural nanocarriers of bioactive molecules that can be orally administered for safe transport through the harsh environment of the stomach directly to lymphoid cells in the GALT and the spleen, rather than the bloodstream. Lila Drittanti, Ph.D., AGS Co-Founder and Chief Operating Officer, explains how MEVs have the potential to be among the first successful oral delivery systems for vaccines and immunomodulatory therapeutics.

January 3, 2023

Lila Drittanti, Ph.D.

Co-Founder and Chief Operating Officer

AGS

Paris, France

Microalgae Extracellular Vesicles (MEV), a New Delivery System, May be the Key to Opening Oral Administration to the Intestine, the GALT and the Spleen.
Upon oral administration, MEVs reach the GALT and, bypassing the first-pass barrier in the liver, reach the spleen. Right-side image: Spleen cells,TEM - ©Thomas Deerinck / NCMIR. AGS©2022

Oral delivery of drugs is preferable to other more invasive forms of administration, such as needle injection and clinic-based infusions. It’s more convenient for patients and less expensive. But oral administration has not been available for biologics (peptides, proteins, DNAs, RNAs), the most innovative drugs for most diseases, because these large therapeutic molecules are degraded by enzymes in the gastrointestinal tract and can’t pass through its multiple layers. 

At AGS we are trying to change that. We are developing microalgae extracellular vesicles (MEVs), a new, universal drug delivery system, that can be loaded with biologics for oral delivery of vaccines, immunomodulatory therapeutics and intestinal disease drugs. MEVs can be loaded with and subsequently deliver all kinds of biologics such as mRNA, siRNA, miRNA, lncRNA, proteins, peptides, oligonucleotides, plasmids, DNA fragments, as well as small chemical molecules.

Extracellular vesicles (EVs) are natural nanoparticles produced by all kinds of cells (including human, animal, plant, and bacteria) to communicate with surrounding cells from the same or different organisms. They are literally nanocarriers of biologically active molecules to cells.

Most mammalian EVs under development as therapeutics act more like a surrogate to cell therapy (as they are aimed at carrying and delivering cargos that bear a strong specificity to the cells at the origin of the EVs), rather than a universal delivery system for loading and carrying a diversity of payloads. Moreover, most EVs from mammalian origin cannot pass the gastrointestinal barrier and are therefore not suitable for the oral delivery of biologics. Alternatively, there are no indications that synthetic lipid nanoparticles (LNPs), which have undoubtedly excelled as a delivery system for intramuscular anti-COVID vaccines, bear any value for oral delivery of biologicals. 

AGS is the first to employ MEVs. AGS’ MEVs are derived from Chlorella, a 2 billion-year-old, fresh water unicellular algae, which has been used for decades as a food supplement and is non-toxic and non-immunogenic in humans. MEVs easily enter targeted cells and make their way into the right cell compartments for proper processing and expression of their therapeutic payloads.

Our animal studies have shown that when administrated orally in a liquid, MEV therapeutics are not degraded by the harsh environment of the stomach’s gastric juices. Instead, the MEVs protect their payloads and migrate into the intestinal lumen where they can be internalized by epithelial cells to release their payload. This property of MEVs makes them attractive for the delivery of payloads suited for the treatment of intestinal diseases such as inflammatory bowel disorders.

MEVs also pass through the epithelial cells to the GALT, the gut-associated lymphoid tissue, which lies throughout the intestine underneath the epithelium. The GALT, part of the immune system, prevents pathogens from entering the bloodstream from the gut.

When MEVs reach the GALT, they enter specific cells of the immune system, such as macrophages and dendritic cells where they accumulate in endocytic vesicles. The dendritic cells or macrophages having internalized the MEVs make their way straight to the red pulp and the white pulp of the spleen. Inside the migrating GALT cells, MEVs are invisible to the liver or to other kinds of first-pass metabolism barriers. Once in the GALT and spleen, antigens payloaded in the MEVs have the potential to activate specific effector immune cells, such as different kinds of lymphocytes, as well as deliver immunomodulatory treatments for illnesses such as autoimmune diseases and cancer.

MEVs do not pass from the intestine to the blood stream, but they go straight to the lymphoid system, and they travel inside lymphoid cells. Thus, the expression “oral delivery” for AGS means “direct access to lymphoid cells in the GALT and the spleen” rather than “delivery to the blood stream.

Left: Upon oral administration, MEVs go straight to the lymphoid system without passing to the blood stream. Right: In vitro tracking of MEV internalized by GALT cells, after oral administration of PKH26 labelled MEV. AGS©2022
Left: Upon oral administration, MEVs go straight to the lymphoid system without passing to the blood stream. Right: In vitro tracking of MEV internalized by GALT cells, after oral administration of PKH26 labelled MEV. AGS©2022

In addition to collecting the MEVs and exo-loading them with biologics, we can engineer the Chlorella cells to produce (endo-load) biologics in the MEVs that are released in the cell culture medium. Endo-loaded MEVs containing therapeutic payloads, such as mRNA, would allow the recurrent production of these medicines, significantly reducing their cost of production.

MEVs can address the major needs of most drug development. In addition to oral administration, we are developing MEVs for the delivery of therapeutics intratracheally, intranasally, topically, and intravenously.

 

Nebulization of the MEVs can be used to target respiratory disorders involving the lungs, and intranasal administration into the brain through the olfactory nerve can be used to deal with many serious brain diseases. Topical administration can be used to treat ophthalmic diseases, through drop-instillation delivery into the eyes, or skin diseases by local administration. Intravenous administration of MEVs targets the liver.

Another advantage of MEVs over other delivery systems is their simplicity of production. All that is required for the production of MEVs is minerals, fresh water and light. Production is eco-friendly and easily scalable for commercial manufacturing.

Successful application of MEVs for oral vaccination and oral delivery of other immunotherapies could make these medicines more accessible to people worldwide and lower their cost. Direct targeting of the spleen by oral administration could make MEV-based oral vaccines more efficacious in activating memory lymphocytes. Oral delivery of vaccines is one of my personal biggest motivations. I believe the future of medicine is prevention, and vaccines are an essential aspect of that effort if we are to improve global health.

ABOUT THE AUTHOR

Lila Drittanti, Ph.D.

Co-Founder and Chief Operating Officer

AGS

Paris, France

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