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

Abstract

ABSTRACT Synthetic catalytic antioxidants offer attractive alternatives to enzymatic redox regulators, yet their biological application is frequently limited by poor stability, formulation challenges, and insufficient control over intracellular localization. Here, we report a lipid conjugation strategy that enables the covalent integration of manganese Salen (EUK) catalysts into phospholipid membranes. A modular synthetic route is established in which a carboxylate‐functionalized EUK derivative is coupled to an amine‐terminated phospholipid tail, yielding a structurally defined phospholipid‐EUK conjugate that retains catalytic activity upon liposome formulation, with controlled catalyst loading and long‐term colloidal integrity. The resulting liposomes exhibit efficient catalytic degradation of reactive oxygen species (ROS) with activity scaling with conjugate content. Importantly, covalent anchoring of the catalyst within the lipid bilayer prevents aggregation and precipitation observed for non‐conjugated analogues. Using an acetaminophen challenged steatotic HepaRG cell model, we demonstrate that lipid conjugation enables intracellular delivery of the catalyst and sustained reduction of elevated ROS levels without inducing cytotoxicity. This effort establishes a chemically precise approach for positioning organometallic catalysts within biomimetic membranes and highlights these conjugates as versatile platforms for controlled intracellular redox modulation.