Small extracellular vesicles designed using click chemistry show promise to target liver failure

A study conducted by Professor Tai Yen Lin at the National Taiwan University highlights the potential of small extracellular vesicle (SEV) therapy and enhances the accuracy of acute liver failure treatment through the application of click chemistry. This study was published in the Journal of Extracellular Vesicles.

Every day, the liver eagerly metabolizes the foods we consume and the medicines we take. However, excessive intake of common analgesics such as acetaminophen (paracetamol) can overwhelm liver function and lead to major damage. In serious cases, this is acute liver failure, a rapidly progressive, life-threatening condition that may require a liver transplant for survival.

To combat acetaminophen overdose, clinicians often administer N-acetylcysteine ​​(NAC). This relieves liver damage. Nevertheless, NACs are not always timely effective, especially in severe cases, and when administered for a long period of time, they can result in potential side effects such as allergic reactions and interference with liver regeneration. In some scenarios, NAC alone is not sufficient to maintain liver function.

To pursue a more effective solution, a research team led by Professor Tai Yen Lin of the National Taiwan University has devised a targeted approach. Instead of traditional medicines, we utilized small extracellular vesicles (SEVs) that promote cell-to-cell communication. SEV transports important molecules such as RNA, proteins, and lipids, and plays an important role in cell healing and communication.

SEVs derived from mesenchymal stromal cells (MSCs) are particularly potent because they can attenuate inflammation, promote regeneration, and support immune homeostasis. However, the key challenge is that injected SEVs do not have target delivery and often accumulate in non-target organs, limiting their therapeutic efficacy.

To address this, Professor Lynn’s team adopted a sophisticated chemical technique called “Click Chemistry,” similar to molecular velcro, which quickly and selectively binds certain molecules without destroying other biological systems. This method is ideal for modifying biological molecules such as SEVs due to aqueous compatibility, high selectivity, and mild reaction conditions.

The team first utilized the sugar-based molecule Ac4mannaz to label vesicles produced by placenta-derived MSCs (PCMSCs) grown under serum-free clinical grade conditions. This labeling stage is now chemically tagged with vesicles called n₃-SEVs, prepared for subsequent modifications.

For targeting, the team designed small antibody fragments that can recognize and bind ASGR1 proteins that are primarily expressed in hepatocytes. This fragment was modified in a complementary chemical group (DBCO) and when mixed with N3-SEV, clicking the exact conjugation of the two components promoted Click chemistry.

The resulting kerseff was a vesicle with a therapeutic payload and accurate liver targeting ability. In animal models, these designed vesicles showed superior homing for damaged liver tissue compared to unmodified SEVs, effectively reducing hepatitis inflammation, reducing damage markers, and promoting tissue repair.

Because of the absence of cells, CAR-SEV avoids many risks associated with whole cell transplantation, such as immune rejection and uncontrolled cell proliferation.

What’s more, the versatility of the platform is notable. By modifying targeting molecules, researchers can direct these vesicles to other tissues and organs, suggesting that the same click chemistry-based strategy can be adapted to develop treatments for various conditions such as cardiovascular disease, cancer, and neuropathy.

“This approach shows that chemical engineering can enable natural cellular messages to be converted into targeted therapies,” says Professor Tai Yen Lin.

“By utilizing clinical grade PCMSCs and using Click Chemistry, we are developing a flexible and safe platform that can be applied to many other diseases in the future.”