A self-deliverable H2O2-responsive tocopherol dimer for enhanced antioxidant and liposomal delivery

Oxidative stress caused by excessive hydrogen peroxide (H₂O₂) plays a central role in skin damage, inflammation, and premature aging, particularly through light-induced photosensitization. Tocopherol (TCP) is a widely used antioxidant in cosmetics, yet its potential in H₂O₂-responsive systems remains underexplored. Here, we report the design and characterization of ditocopheryl peroxalate (TOT), a novel tocopherol dimer linked via an H₂O₂-cleavable peroxalate bond. TOT remains stable under physiological conditions but selectively degrades in response to H₂O₂, simultaneously scavenging H₂O₂ and releasing two TCP molecules. TOT exhibited comparable radical scavenging activity to TCP but showed superior H₂O₂-scavenging efficiency, stronger antioxidant and anti-inflammatory effects in H₂O₂-stimulated cells, and excellent biocompatibility. Its rigid, linear structure promoted alignment within dipalmitoylphosphatidylcholine (DPPC) bilayers, enabling formulation of stable, H₂O₂-responsive liposomes with effective cellular uptake. These findings highlight TOT as a multifunctional, self-degradable antioxidant with strong potential as a cosmetic ingredient for protecting skin from oxidative and phototoxic damage.