Energy regenerator: the liver will repair itself with the help of microRNA particles

Russian scientists have presented an innovative technology for liver protection and repair based on biocompatible nanoparticles and microRNA molecules. The system has shown high efficiency in acute and chronic organ damage, including fibrosis and paracetamol overdose. Experts note that with successful completion of all stages of testing, the development can be used to treat hepatitis and other liver diseases, and in some cases even reduce the need for transplantation. At the same time, they emphasize that the technology is at an early stage, and scientists have a long way to go through research and testing before its widespread introduction into clinical practice.

microRNAs for liver treatment

Scientists have created a new system for delivering microRNA molecules to the body based on nanoparticles, which can simultaneously reduce liver damage and stimulate its recovery. Such particles protect the active substance from destruction in the blood and help deliver it directly to the target cells. The development was presented by scientists from Sechenov University together with researchers from the Volga Research Medical University (PIMU), ITMO and MIPT.

Similar approaches underlie nanomedicine, a field in which drug molecules are delivered to the body using nanometer—sized particles tens of thousands of times smaller than the thickness of a human hair, scientists told Izvestia.

— The development of a microRNA-based therapy makes it possible to influence several key points of pathogenesis at once. In this work, the protective effect of these molecules was confirmed in both acute and chronic liver damage. This approach makes it possible not only to reduce the manifestations of pathological changes, but also to stimulate the natural, physiological processes of tissue regeneration," Petr Timashev, scientific director of the Sechenov University Research Laboratory, told Izvestia.

To deliver microRNA-200a to liver cells, the scientists synthesized biocompatible nanoparticles based on polylactic acid (PLA) and auxiliary polymers. They protect the microRNA from destruction and ensure its gradual release inside the cell, allowing the activation of protective molecular mechanisms.

The researchers tested the effectiveness of the new technology in two pathology models. In the regeneration model against the background of acute liver damage caused by an overdose of paracetamol, the introduction of nanoparticles with microRNA-200a significantly reduced the toxic damage to tissues, normalized the level of enzymes and restored the ability of hepatocytes to divide.

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In the second series of experiments, the team studied the effect of therapy in a model of regeneration in chronic pathology — fibrosis. In this case, the treatment significantly reduced the accumulation of collagen in the liver tissue and reduced the severity of fibrosis by two stages according to the Metavir scale, a clinical system for assessing the degree of organ damage. At the same time, there was a restoration of the metabolic activity of cells and increased tissue regeneration.

According to the researchers, activation of the Keap1/Nrf2 signaling pathway, which protects cells from oxidative stress and triggers cellular repair processes, plays a key role in the therapeutic effect.

A promising cure for liver diseases

The authors emphasized that the proposed technology can become the basis for new treatments for various liver diseases. In the future, they plan to continue preclinical research and evaluate the prospects for clinical application of the developed platform.

Scientists have created a nanoparticle-"courier": it invisibly penetrates into hepatocytes and delivers there the microRNA-200a molecule, the "instruction" for recovery, molecular biologist Arina Kholkina told Izvestia. This instruction triggers the innate protective pathway Keap1/Nrf2, which dampens oxidative stress and at the same time inhibits the formation of scar tissue. This is how the liver starts to repair itself.

— The approach has already worked in two scenarios: in acute paracetamol poisoning, it saved cells from death and started their division, and in chronic fibrosis it reduced scarring by two stages. This technology is potentially applicable for alcoholic and non-alcoholic fatty diseases, toxic and viral hepatitis, as well as for regeneration after removal of part of the liver. This is not an external cell replacement, but the awakening of its own renewal program through controlled regeneration instead of transplantation," the expert said.

The novelty in this work is not so much related to the polymer itself or even a single microRNA, but rather to their functional combination and the biological context of the application, Albert Rizvanov, head of the Personalized Medicine Center of Excellence at Kazan (Volga Region) Federal University, told Izvestia.

— Innovation here is rather "systemic": This is an optimized delivery platform that protects microRNAs from degradation, controlled release, and functional activity inside liver cells, which remains one of the main barriers to RNA therapy.

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Potentially, such systems may be in demand for drug-induced organ damage, non-alcoholic fatty liver disease, viral hepatitis and fibrosis of various etiologies, where inflammation and oxidative stress play a key role, Albert Rizvanov emphasized. However, the main limitation remains the same for all microRNA therapies: the need for precise delivery to the desired cell type, dose control and long-term effects, as well as reproducibility at scale. Therefore, we are still talking about a promising platform, and not about a ready-made clinical solution, the specialist noted.

The results of the study are published in the Biomaterials journal.