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Lipid Nanoparticles Deliver Promise for Liver Disease Therapies

The success of messenger RNA (mRNA)-based vaccines, such as ones for COVID-19, depends on their delivery vehicle—a high-tech bubble of lipids (fats) called a lipid nanoparticle (LNP) encasing an inner package of fragile genetic material. This protective coating enables the mRNA to safely reach its destination inside target cells, where it produces viral proteins that train the immune system to resist infection. However, the potential medical applications of LNPs extend well beyond vaccines. Two groups of scientists have tested LNPs in mouse models to deliver treatments for multiple forms of liver disease, including liver fibrosis, nonalcoholic fatty liver disease, and drug-induced liver injury.

Targeted Hormone Treatment Transforms Liver Cells into Fibrosis-fighting Superheroes:

New research in mice shows the potential for LNP-based therapies that incorporate a dynamic duo—the hormone relaxin and liver macrophage cells—on a mission to deactivate the liver’s fibrosis-promoting cells. Liver fibrosis (scarring associated with tissue injury), and its advanced stage of cirrhosis, are common health problems that develop over the course of diseases such as fatty liver disease. A cast of characters play a role in either activating or repairing liver fibrosis. Hepatic stellate cells are key players in liver fibrosis. When activated by liver injury, they participate in the wound healing response and contribute to scar tissue formation in the liver and subsequent fibrosis. Some other factors work to limit fibrosis, potentially by inactivating stellate cells, including the hormone relaxin, which is primarily known for its role in pregnancy-related changes in the female reproductive system. And finally, some cells act as a double agent like the liver macrophage, a type of immune cell with the ability either to promote inflammation or to foster tissue repair.

Scientists used an animal model of liver fibrosis to unravel these interactions and unlock their therapeutic potential by employing the powerful LNP delivery technology. Male mice given a toxic chemical for several weeks developed liver injury and fibrosis. But this fibrosis could be reversed by two weeks of daily injection with LNPs delivering a gene-based therapy that boosted relaxin production in liver cells. However, when the researchers studied hepatic stellate cells in culture, they were surprised that the relaxin-treated cells remained active and fibrosis-promoting. This finding suggested that the cells in culture were missing essential cues from their environment to cause inactivation in response to relaxin. This prompted the scientists to identify relaxin receptors on the liver macrophages in mice and in samples taken from men with cirrhosis. Upon relaxin binding to its receptor, the macrophages transformed from fibrosis promoters to fibrosis-fighting cells that secrete small LNP-like packages of microRNAs (small pieces of genetic material that control the activity of other genes), which then targeted hepatic stellate cells and blocked their ability to induce fibrosis. The scientists engineered a different type of LNP to carry one of the microRNAs and delivered these along with the LNPs containing the relaxin gene. This combination treatment was even more powerful in reversing fibrosis, both in the liver fibrosis model and in a mouse model of nonalcoholic fatty liver disease.

These studies highlight the important role of macrophages in relaxin-mediated amelioration of liver fibrosis in diseases such as nonalcoholic fatty liver disease, through inactivating hepatic stellate cells. This work shows the potential for approaches combining gene therapy with LNP-based nanotechnology that directly target liver cell networks to provide new treatment options for liver fibrosis.

Potential Regeneration Therapy for Liver Injury Activates Timely Burst of Growth Factors:

Scientists have showcased the ability of LNP-encapsulated mRNA to deliver controlled bursts of growth factors that boost regeneration as a potential therapy for acute and chronic liver injury. Effective therapies are lacking for common forms of liver disease, such as nonalcoholic fatty liver disease and cirrhosis. People with acute or chronic forms of liver injury can have a limited window of opportunity in which a therapy can curb damage and restore function of this vital organ. An ideal treatment would need to accomplish this feat of regenerating the liver during a narrow time frame and in a safe way.

Researchers designed LNP capsules containing mRNA that was modified to increase its stability to produce two growth factors, called hepatocyte growth factor and epidermal growth factor. When injected into female mice in these studies, the capsules were delivered to liver cells as their primary target, which manufactured the growth factors for approximately 3 days. In healthy mice, the short-term hepatic growth factor production boosted liver regeneration by ramping up liver cell production that typically maintains the organ. Furthermore, in mice fed a diet resulting in features of chronic liver injury similar to nonalcoholic fatty liver disease, treatment with LNPs containing mRNAs for both growth factors reversed fat deposits in the liver and enhanced liver function, more than in mice given a control LNP vehicle. Similarly, in a mouse model of an acute liver injury due to overdose of the drug acetaminophen, treatment with both growth factors in the mRNA delivery vehicles accelerated liver regeneration and lowered liver enzymes to normal levels.

This research shows the usefulness of LNP-encapsulated mRNA for delivering discrete bursts of growth factors as a possible, safe therapy for promoting liver regeneration in animal models of acute and chronic liver injury. Future studies will explore whether this new treatment approach can be translated to the clinic to prevent liver disease progression and restore function.

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