A Self-Deliverable H₂O₂-Responsive Tocopherol Dimer for Enhanced Antioxidant and Liposomal Delivery

Oxidative stress induced by excessive hydrogen peroxide (H₂O₂) is a critical pathological factor in skin aging, inflammatory disorders, and photodamage. While tocopherol (TCP) is a gold-standard antioxidant in cosmetics, its potential in H₂O₂-responsive systems remains underexplored. In this study, we report the design and characterization of ditocopheryl peroxalate (TOT), a novel tocopherol dimer linked via a H₂O₂-cleavable peroxalate linkage. TOT remains chemically stable under physiological conditions but undergoes selective chemiluminescence-like degradation upon exposure to H₂O₂, simultaneously scavenging H₂O₂ and liberating two TCP molecules. Notably, TOT demonstrated superior H₂O₂-scavenging efficiency and enhanced antioxidant and anti-inflammatory effects in H₂O₂-stimulated cells compared to monomeric TCP, while maintaining excellent biocompatibility. Structural analysis revealed that the rigid, linear configuration of TOT facilitates seamless integration into dipalmitoylphosphatidylcholine (DPPC) bilayers, yielding highly stable H₂O₂-responsive liposomes. These findings highlight TOT as a sophisticated multifunctional antioxidant platform for advanced cosmeceutical applications targeting photo-induced oxidative damage.