Liver Failure Treatment: AI-Cells for Targeting Hepatic Macrophages

Acute liver failure (ALF) is a devastating condition with high mortality rates, primarily due to the rapid loss of liver function and consequent multi-organ failure, particularly in individuals without preexisting liver disease. The hallmark of ALF is the abrupt loss of hepatic function, typically occurring within days or weeks, and is often accompanied by encephalopathy (altered mental status) and impaired blood clotting.  Acute liver failure represents a critical medical emergency with complex pathophysiology and potentially fatal outcomes. Rapid diagnosis and aggressive treatment, including liver transplantation in severe cases, are crucial. Research into new treatments like is vital for improving survival rates and patient outcomes in ALF.  The current therapeutic paradigm for ALF, largely reliant on N-acetyl cysteine and liver transplantation, faces significant limitations including donor shortages and the risks associated with long-term immunosuppression. This creates an urgent need for novel, effective treatments. Itaconic acid, a metabolite produced by certain types of fungi, has recently attracted interest in the medical community due to its potential therapeutic benefits. In the context of acute liver failure, the therapeutic benefits of itaconic acid emerging research suggests possible mechanisms through which it could be beneficial.  Itaconic acid has been shown to possess anti-inflammatory properties. Itaconic acid also offer antioxidant benefits, helping to neutralize free radicals and reduce oxidative stress in liver cells. Moreover, Itaconic acid can influence immune system responses and mitigating the progression of liver damage. Additionally, Itaconic acid might protect mitochondria or improve their function, which is critical for cell survival and repair, especially in the liver as well as  inhibiting fibrosis, a process that can follow liver injury and lead to chronic liver disease.

In a new study published in Cell Reports Medicine by Na Yin, Wenjun Zhang, Xiao-Xin Sun, Runxiu Wei, Qiang Yang, Fengming He, Changrui Li, Ling Guo, and led by Professor Min Feng from the School of Pharmaceutical Sciences at Sun Yat-Sen University focused on addressing ALF. They developed a novel therapeutic approach using artificial apoptotic cells loaded with itaconic acid (AI-Cells) to target hepatic macrophages, which play a significant role in the progression of ALF. The role of hepatic macrophages in liver pathology, specifically in the context of cytokine storms and inflammation-driven liver damage, is a critical aspect of this study. The innovative approach of targeting these cells offers a new pathway for therapy. The development of AI-Cells, which mimic apoptotic cells to target macrophages selectively, represents a significant leap in drug delivery systems, addressing the challenge of targeted therapy in hepatic disorders. The researchers engineered AI-Cells and loaded them with itaconic acid, resulting in AI-Cells. This was done to ensure targeted delivery of itaconic acid to hepatic macrophages. The AI-Cells were designed to mimic natural apoptotic cells in both their surface topology and membrane composition, enhancing their uptake by macrophages. AI-Cells were shown to preferentially localize in the liver, particularly in hepatic macrophages. This was critical because macrophages are central to the inflammatory processes driving ALF.

The authors tested the efficacy of AI-Cells in mouse models of acetaminophen-induced ALF. This model is representative of drug-induced liver injury in humans. They demonstrated that AI-Cells has high affinity for the liver and were predominantly taken up by hepatic macrophages. This selective localization was crucial for their therapeutic effect. The study found that intravenous administration of AI-Cells modulated the inflammatory response of macrophages. AI-Cells acted on caspase-1 to inhibit the NLRP3 inflammasome-mediated cleavage of pro-IL-1β, preventing its conversion into the active form. AI-Cells significantly protected the liver from ALF induced by acetaminophen. They reduced liver damage and improved survival rates in the mouse models. Remarkably, AI-Cells induced a state of “memory” in hepatic macrophages. These trained macrophages exhibited an anti-inflammatory profile, which was beneficial in preventing overproduction of IL-1β when liver reinjury occurred. The team suggested that the AI-Cells’ ability to finely control inflammatory responses and orchestrate liver homeostasis has implications beyond ALF, potentially affecting the treatment of various types of liver failure.

The study significantly contributes to the fields of drug delivery and precision medicine. The use of AI-Cells to deliver itaconic acid directly to hepatic macrophages demonstrates an advanced level of precision in drug targeting, which is crucial for maximizing therapeutic efficacy while minimizing systemic side effects. This approach could be a blueprint for developing treatments for other diseases where targeted therapy is paramount. The implications of this research extend beyond ALF to other types of liver failure and potentially to a range of inflammatory and autoimmune diseases. By demonstrating the feasibility and efficacy of modulating innate immune responses in the liver, this study opens new avenues for research and therapy in a range of hepatic illnesses. While the study presents a promising new approach to treating ALF, it also lays the groundwork for future research. Key areas for further investigation include the long-term effects and safety profile of AI-Cells, their effectiveness in human subjects, and their potential application in other inflammatory conditions. Additionally, scaling up production and navigating regulatory approvals will be crucial for translating this research from the lab to the clinic.

In conclusion, the research by Professor Min Feng and colleagues represents a novel approach in liver disease treatment. By innovatively targeting hepatic macrophages with AI-Cells, they demonstrated a potential new therapeutic strategy for ALF and possibly other liver diseases. Their findings offer insights into controlling inflammation in liver diseases and present a promising avenue for future therapies.