The sebaceous membrane and stratum corneum play crucial roles in shielding against external pollution and regulating the transdermal absorption of foreign substances in daily life[1]. The primary challenge faced by the skin barrier is addressing compromised functions due to factors such as skin aging, sensitivity, and pigmentation, which can escalate to conditions like dermatitis, eczema, and other skin-related diseases[2], [3]. Oxidative stress, one of the most common reasons of skin injury, manifest a negative effect of reactive oxygen species (ROS) in the body and is considered as a major contributor to aging and disease[4], [5], [6].

Copper is essential for all eukaryotic organisms, and a variety of biochemical reactions require copper to catalyze[7]. It serves a signaling function that promotes the differentiation of stem cells, aiding in the repair of injured skin cells[8], [9]. Copper peptide (GHK-Cu) acts as an "on/off switch" that inhibits inflammation, promotes cell-extracellular matrix interactions, stimulates collagen synthesis, reduces oxidative damage and rejuvenates damaged skin cells[10].

A notable challenge in previous findings lies in the practical application of GHK-Cu, marked by certain inconveniences[11]. Generally, the chelation of divalent copper ions with tripeptide-1 results in insufficient stability. GHK-Cu may be prone to decomposition by skin proteases due to its limited enzyme resistance properties, making copper easily exposed to the external environment. In addition, copper exhibits a significant interaction force with the skin phospholipid structure. Furthermore, GHK-Cu as a water-soluble peptide, it is tough to effectively penetrate the skin epidermis and reach the dermis to make its effects. Therefore, there is an urgent need for a useful method to solve the above problems.

A variety of drugs show a series of problems in biological in vivo and clinical settings such as targeting as well as poor biocompatibility, low solubility, cellular and central nervous system toxicity, and short in vivo circulation time[12]. Nanocarriers have been developed for drug delivery applications[13]. Nanocarriers are sub-micro unit carrier delivery systems with dimensions in the nanometer microcosmic category, which are usually considered as safe inactive media with good biocompatibility[14], as well as overcoming the endosome-lysosome mechanism, and are able to circulate for a long period of time for sustained release of the drug in the organism. Nanoliposomes (NLP), which are nanocarriers composed of lipid bilayers, have been diffusely used for drug delivery systems due to the characteristics of biocompatibility and drug loading capacity[15], [16]. Liposomes exhibit high flexibility and deformability, attributes achieved by incorporating various surfactants and polyols into the lipid bilayer[17]. The core lumen of the vesicle is capable of carrying water-soluble components, while the lipid-soluble active ingredient is encapsulated in the middle of a bilayer of lipid molecules[18]. NLPs enhance the efficiency of uptake through adsorption, lipid exchange, and endocytosis[19]. Within NLPs, it can control the release time of the drug and promote skin absorption, and the drug can more easily pass through the surface of the skin to reach the dermis[20], [21].

Building upon the traditional Chinese concept of rigidity and flexibility, this study systematically prepared a series of GHK-Cu liposomes (GHK-Cu@LP) by employing polyols with varying molecular chain lengths as embedding modification ligands. The purpose of experiment investigated the effects of the molecular chain length of the polyol and the amount of GHK-Cu on the particle size and distribution, encapsulation rate and stability of GHK-Cu@LP. Furthermore, the research comprehensively assessed the enzymatic resistance, skin permeability, and in vitro safety of GHK-Cu@LP. Additionally, a preliminary investigation was conducted into the antioxidant and anti-inflammatory mechanisms of GHK-Cu@LP. The anticipation is that further exploration of GHK-Cu@LP will contribute to advancements in addressing skin aging, sensitivity, and pigmentation.