Lysine‐Based Ionic Liquid Enables Peptides to Reverse Skin Photoaging: From Leaves to Roots

Abstract Peptides and proteins are pharmacologically active and highly safe; however, their local delivery remains a challenge in the field of drug delivery. Based on this, a novel lysine‐based ionic liquid via proton transfer between lysine and malic acid that can overcome the difficulties in the application of copper peptides is developed. Density functional theory, molecular docking simulations, and experimental validation demonstrate the chemical stability of this ionic liquid. Furthermore, by combining it with a vegetable oil system, a biocompatible lysine‐based ionic liquid microemulsion system is constructed, which perfectly combines the high viscosity of ionic liquids and low viscosity of microemulsions. Multi‐dimensional analysis shows that the system not only leads to a dramatic elevation in the local penetration of copper peptides, but also enables copper peptides to effectively suppress skin aging. In addition, transcriptome sequencing analysis reveals that the system primarily regulates p53, p16 , and ECM‐related signaling pathways to combat photoaging in the skin. Overall, a noninvasive, efficient, and convenient anti‐aging system with enormous potential is developed for the clinical prevention and treatment of skin photoaging.