Sustained Activation of Nrf2 Antioxidant Pathway by Flexible Liposome Based on Low Phase Transition Temperature to Delay Skin Aging

Abstract Intrinsic skin aging and photoaging induce alterations in skin morphology and increase the risk of skin diseases. Reactive oxygen species (ROS) are key contributors to these processes, and nuclear factor erythroid 2‐related factor 2 (Nrf2), a central antioxidant transcription factor, represents a promising therapeutic target for combating oxidative stress. Therefore, activation of Nrf2 is anticipated to alleviate oxidative stress, preserve cellular homeostasis, and restore dermal fibroblast function by upregulating antioxidant enzymes. In this study, the Nrf2 agonist dimethyl fumarate (DMF) is selected as a model drug, and constructed flexible liposome FL@SC by adding anionic surfactants to enhance the skin penetration, and achieved sustained activation of Nrf2 through the controlled release of DMF, while improving the concentration dependence of DMF on cell protection. The results showed that Nrf2 activation ex erted remarkable anti‐aging effects in two skin aging models induced by D‐galactose and UVB. FL@SC significantly enhanced the penetration and retention of DMF in the dermis, thereby inhibiting hallmarks of skin aging, including structural disorganization, flattening of epidermal rete ridges, and collagen degradation. Collectively, this study presents a viable strategy for delaying skin aging by alleviating oxidative stress in dermal fibroblasts via the targeted delivery of Nrf2 agonists using flexible liposomes.