TPGS-functionalized liposomal formulation for the transdermal delivery of ellagic acid.

The pursuit of effective anti-aging interventions remains a significant challenge in dermatological research. Ellagic acid (EA), a natural polyphenol with demonstrated anti-skin-aging properties, faces limitations in therapeutic application due to poor percutaneous absorption. To address this challenge, we developed TPGS-functionalized liposomes (EA-TPGS-L) through systematic optimization using a Box-Behnken design, achieving an encapsulation efficiency of 94.19% and an optimal particle size of 152.50 nm. MD simulations revealed that TPGS enhances skin permeation by spontaneously inserting its hydrophobic domain into the stratum corneum, thereby disrupting the ordered lipid packing and specifically reducing the free energy barrier within the hydrophobic core of the bilayer. The optimized EA-TPGS-L formulation exhibited comprehensive anti-aging effects, including potent antioxidant activity with greater radical scavenging capacity compared to free EA and EA-L, significant inhibition of key aging-related enzymes, and effective cellular protection evidenced by a reduction in lipid peroxidation. Furthermore, skin-on-a-chip evaluations demonstrated the formulation's ability to promote tissue remodeling, showing 84.11% recovery of type I collagen while effectively regulating oxidative stress markers. These collective findings establish TPGS-modified liposomes as a promising transdermal delivery platform that overcomes the skin barrier while amplifying the anti-aging efficacy of natural polyphenols like EA, offering significant potential for advanced dermatological and cosmeceutical applications.