Combating Reactive Oxygen Species (ROS) with Antioxidant Supramolecular Polymers

Reactive oxygen species (ROS) are highly damaging biological molecules significantly upregulated following major injuries or diseases such as heart attack, burn injury, and stroke. Despite promising preclinical results, traditional small-molecule antioxidant therapies have had limited success in clinical applications. In this study, we employed a macromolecular approach to combat ROS, demonstrating that tethering the potent biological antioxidant, glutathione, to a peptide amphiphile effectively consumes harmful extracellular radicals while preserving antioxidant and polymeric functionality. By neutralizing these radical species, we can protect vulnerable cells from acute ROS toxicity. This was validated by assessing cellular oxidative damage and survival in cell lines stimulated with tert-butyl hydroperoxide (tBHP) to induce ROS production. The antioxidant nanofibers achieved cell rescue at concentrations an order of magnitude lower than molecular glutathione, a direct result of the extracellular localization and enhancement in the proximal concentration of the glutathione moieties along the supramolecular polymer. These antioxidant supramolecular polymers offer proof of principle for a macromolecular strategy to combat the damaging effects of extracellular ROS associated with disease and injury, showcasing their efficacy at low concentrations and maintaining antioxidant capabilities when in the gelled state, providing for the potential of an antioxidant tissue regenerative scaffold.