Engineered Lipids for Intracellular Reactive Oxygen Species Scavenging in Steatotic Hepatocytes

Intracellular reactive oxygen species (ROS) in steatotic cells pose a problem due to their potential to cause oxidative stress and cellular damage. Delivering engineered phospholipids to intracellular lipid droplets in steatotic hepatic cells, using the cell's inherent intracellular lipid transport mechanisms are investigated. Initially, it is shown that tail‐labeled fluorescent lipids assembled into liposomes are able to be transported to intracellular lipid droplets in steatotic HepG2 cells and HHL‐5 cells. Further, an antioxidant, an EUK salen–manganese derivative, which has superoxide dismutase‐like and catalase‐like activity, is covalently conjugated to the tail of a phospholipid and formulated as liposomes for administration. Steatotic HepG2 cells and HHL‐5 cells incubated with these antioxidant liposomes have lower intracellular ROS levels compared to untreated controls and non‐covalently formulated antioxidants. This first proof‐of‐concept study illustrates an alternative strategy to equip native organelles in mammalian cells with engineered enzyme activity. The level of intracellular reactive oxygen species (ROS) in steatotic cells is lowered by delivering tailored phospholipids to lipid droplets via intrinsic intracellular transport mechanisms. Fluorescent lipids and a EUK salen–manganese derivative conjugated to lipids, both formulated as liposomes, effectively target intracellular lipid droplets in steatotic HepG2 and HHL‐5 cells, leading to reduced intracellular ROS levels.