Enhanced Skin Permeation of Anti‐Aging Peptides Using Bioactive Ionic Liquids at Low Concentrations

Abstract Delaying aging is an eternal goal for humanity. Acetyl hexapeptide‐8 (AHP‐8) is an effective skin anti‐aging drug that locally interrupts the signal transmission of muscle contractions and promotes collagen production, thus smoothening wrinkles. However, its high molecular weight and strong hydrophilicity limit its skin permeation capacity. To solve this problem, an ionic liquid with excellent bioactivity, MAC, is synthesized from l ‐malic acid and l ‐carnitine and used as a permeation enhancer to improve the anti‐aging effects of AHP‐8. The ratio of MAC's components is optimized based on density functional theory calculations and cytotoxicity experiments. Low concentrations of MAC significantly increase AHP‐8 transdermal delivery, reaching a maximum at 5‐10 wt% MAC. The pro‐permeation mechanism of MAC is investigated using molecular dynamics simulations, and the penetration enhancement and anti‐aging performance of AHP‐8 are demonstrated by conducting cellular, animal, and clinical experiments. The results show that MAC/AHP‐8 outperforms AHP‐8 in terms of collagen and hyaluronic acid synthesis, anti‐inflammation, anti‐oxidation, and inhibition of muscle contraction, thus significantly reducing the number and area of wrinkles and increasing skin moisture and elasticity. This study presents MAC as a simple and efficient transdermal vehicle for the clinical application of AHP‐8.