Editors' ChoiceNanomedicine

Nano livers: A sobering discovery

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Science Translational Medicine  25 Apr 2018:
Vol. 10, Issue 438, eaat4479
DOI: 10.1126/scitranslmed.aat4479

Abstract

Hepatocyte-mimicking nanocapsules carrying key liver enzymes reduce blood alcohol concentration in intoxicated mice.

Let’s all take a moment to appreciate our livers—working endlessly to deal with our excesses. However, sometimes a liver needs a little help. This is especially the case in acute alcohol intoxication caused by excessive alcohol consumption, which takes up 8 to 10% of emergency room admissions and for which there is currently no treatment other than supportive care.

To address this problem, Xu et al. have ingeniously designed a hepatocyte-mimicking nanocapsule, containing the alcohol catabolic enzymes alcohol oxidase (AOx), catalase (Cat), and aldehyde dehydrogenase (ALDH). AOx converts alcohol to acetaldehyde and hydrogen peroxide (metabolized by Cat), with acetaldehyde converted to acetate by ALDH. The nanocapsule design increases the thermal and proteolytic stability of the enzymes and readily allows for uptake into hepatocytes, as well as in circulating macrophages, which can carry the nanocapsules to the liver. The authors also show that AOx and Cat are in close proximity to each other within the nanocapsule and remain in close proximity upon trafficking via endosomal pathways in the cell without causing hepatotoxicity.

In alcohol-intoxicated mice, the nanocapsules accumulated in the liver in less than 4 hours after intravenous administration. Two hours after administration, blood alcohol concentration was significantly lower compared with untreated controls. Importantly, blood acetaldehyde levels remained low, contributing to liver protection, though a few markers of organelle stress were elevated due to the therapy. Although the nanocapsules reduced alanine amino transferase (a marker of liver damage) in alcohol-intoxicated mice fed a Western diet, they could not prevent hepatic fat accumulation. This suggests the hepatocyte-mimicking nanocapsules may not be enough to reverse the liver damage caused by alcohol consumption in combination with a poor diet.

The authors acknowledge that there is more work needed to increase applicability to the patient. For example, dose-response studies and formulations with altered release kinetics to reduce short-term stress profiles, as well as safety testing in larger species are needed. That being said, the approach as a whole holds great promise in the field of toxicology. By using targeted enzyme-containing nanocapsules, a wide range of toxic exposures (both self-inflicted and otherwise) could be more rapidly treated.

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