Transdermal drug delivery system (TDDS) has been one of the most popular dosage forms expected to replace oral administration [1], [2], [3]. At present, drug-in-adhesive systems (DIAS) have been extensively applied due to their simple structure, ease of production and good patient compliance [4,5]. It is well known that adhesives are the most critical components in DIAS [6] for their outstanding adhesive strength, capacity to carry drugs, and controlled release of medications. [7].

Currently, the two major types of adhesives commonly used in DIAS include hydrogels and pressure-sensitive adhesives (PSAs), each with its characteristics [8,9]. Hydrogel adheres to the skin under pressure without residue after peeling owing to its good adhesive and mechanical properties [10,11]. Typical hydrogels include polyethylene glycol (PEG), high molecular weight polyvinylpyrrolidone, polyacrylamide, polydopamine, and their derivatives [12,13]. For example, Jung et al. developed hydrogels using polyacrylamide/polydopamine and mesoporous silica nanoparticles, which resulted in an adhesion energy of 15.3 J/m2 [14]. PSAs are distinguished for their ability to load and release drugs [15]. The commonly used pressure sensitive adhesives are mainly classified as polyisobutylene, silicone and acrylate [16]. Acrylate PSAs are the most commonly used adhesives owing to their good physicochemical stability and drug compatibility [17]. In addition, acrylate PSAs alter physical properties such as adhesive properties and controlled release ability due to monomers with different functional groups [15]. However, in recent years, with the continuous updating and development of adhesives, hydrogels still face challenges such as drug-carrying capacity and water dissipation [18,19]. And PSAs face many problems such as adhesion, mechanical properties and poor skin compatibility due to their strong lipophilicity [20,21]. This leads to problems such as shedding or skin sensitivity if used for long periods of time. Therefore, for adhesive in DIAS, a hydrophilic polymer with strong adhesion, superior mechanical properties and higher drug compatibility is necessary required.

In recent years, several biologically inspired materials have been constructed. The products or biomaterials based on silk proteins and chemically active polyethylene glycols (PEGs) exhibit strong adhesive properties and have been widely applied in numerous biomedical fields over the past few decades [22,23]. The exceptional biocompatibility and chemical versatility make such polymers compatible with a wide range of biomedical applications. This class of polymers is based on silk proteins and polyethylene glycol, which in turn provides a better binding ability to drugs due to a large number of hydrogen bond-forming action sites in the polyethylene glycol chain segments within the polymer [24,25]. It has been reported to have good histocompatibility and adhesion properties and has already made a significant contribution in areas such as wound healing [26]. In addition to the concern about the lack of adhesion of adhesive, balancing the adhesion and cohesion of adhesive is another urgent issue to be solved, because improving one property often comes at the expense of the other [27,28]. The adhesive with insufficient cohesion is very soft, unable to maintain a proper balance of adhesion between the adhesive and the skin. Consequently, it cannot be completely removed from the skin surface, resulting in the occurrence of the "dark ring" phenomenon [29]. Similarly, the “dark ring” phenomenon can lead to dosage inaccuracies [30]. For these reasons, due to its flexible and environmentally friendly operation [31], [32], [33], [34], [35], [36], a metal coordination strategy was proposed and different metal ions (e.g., Fe3+, Cu2+, Mg2+, Zn2+, and Ca2+) were selected to enhance the cohesion of adhesive by coordination of metal ions with silk proteins. However, the metal ions vary in size, binding affinity, coordination geometry, coordination number and charge density, thus increasing the cohesion of adhesive to different degrees.

In this study, a high-adhesive adhesive, labelled as PHT-SP, was prepared by expanding polyethylene glycol and silk protein as the main chain through a nucleophilic addition reaction of hexamethylene diisocyanate and TMP. Then, PHT-SP-Cu2+ was prepared by introducing Cu2+ into PHT-SP. The synthesis of PHT-SP-Cu2+ and the formation of the internal Cu2+-p-π conjugation network were successfully verified by using SEM, 13C NMR, FTIR and XPS. Then, the adhesion and mechanical properties of PHT-SP-Cu2+ were comprehensively investigated by static shear, 180° peel and tack tests. In addition, the adhesion tests of PHT-SP-Cu2+ to porcine and human skin were performed by using commercial DURO-TAK® 87-4098 as a control. The molecular mobility of PHT-SP-Cu2+ was evaluated by thermodynamic and rheological analyses. The interactions of the adhesive with the skin surface were analyzed by surface energy and ATR-FTIR. Ketoprofen was chosen as a model drug to be loaded into PHT-SP-Cu2+ and its drug loading capacity was explored by polarized light microscopy. The α-helix facilitated release-acting substrates were investigated by molecular dynamics simulations, Flory-Huggins interaction parameter and FT-IR. In addition, the release of ketoprofen into the skin and the body was also analyzed by Raman confocal microscopy imaging and in vivo pharmacokinetic experiments. Finally, the biosafety was investigated by observation of edema in the sampled area, in vivo erythema analysis and histological examination. The PHT-SP-Cu2+ provided an effective new strategy for the development of adhesive with high adhesion and cohesion for TDDS.