A Lipid-Conjugation Strategy for Intracellular Reactive Oxygen Species Control in Hepatic Cells

Area of Science:

• Biomaterials Science
• Catalysis
• Cell Biology

Background:

• Synthetic catalytic antioxidants are promising alternatives to enzymes but face challenges in stability, formulation, and cellular targeting.
• Controlling the localization and stability of synthetic catalysts within biological systems is crucial for their therapeutic application.

Purpose of the Study:

• To develop a lipid conjugation strategy for integrating manganese Salen (EUK) catalysts into phospholipid membranes.
• To create stable, catalytically active liposomes for controlled intracellular delivery and reactive oxygen species (ROS) scavenging.

Main Methods:

• A modular synthetic route was used to couple a carboxylate-functionalized EUK derivative to an amine-terminated phospholipid tail.
• Liposomes were formulated with the resulting phospholipid-EUK conjugates, and their catalytic activity, stability, and cellular uptake were assessed.
• An acetaminophen-induced steatotic HepaRG cell model was employed to evaluate intracellular ROS reduction and cytotoxicity.

Main Results:

• Lipid conjugation yielded structurally defined phospholipid-EUK conjugates that retained catalytic activity within liposomes.
• The liposomes demonstrated efficient ROS degradation, with activity proportional to conjugate loading and improved stability compared to non-conjugated catalysts.
• Intracellular delivery and sustained ROS reduction were achieved in a cell model without inducing cytotoxicity.

Conclusions:

• Lipid conjugation provides a chemically precise method for incorporating organometallic catalysts into biomimetic membranes.
• Phospholipid-EUK conjugates represent a versatile platform for targeted intracellular redox modulation and therapeutic applications.
• This strategy overcomes limitations of synthetic antioxidants, paving the way for enhanced biological applications.