In this work, imidazolium ionic liquids (imidazolium ILs) were employed as the novel chemical permeation enhancers (CPEs) and their performances and mechanisms of action were deeply investigated. Testosterone was used as a model drug to investigate the transdermal delivery enhancement of twenty imdidazolium ILs. The results suggested that the promotion activity connected to the structure and composition of the ILs. The quantitative structure–activity relationship (QSAR) model revealed a good linearity between the electronic properties of ILs and their enhancements. Furthermore, the transepidermal water loss (TEWL) and scanning laser confocal microscope (CLSM) examinations showed the strong improvement of ILs on skin barrier permeability, which were well correlated with the drug penetration profiles. The total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and atomic force microscope (AFM) evaluations of skins indicated that the ILs can disrupt the regular and compact arrangements of the corneocytes, change the surface properties of stratum corneum, and make the skin structure more permeable. Our work demonstrated the significant skin permeation promotion profiles of the imidazolium ILs, which are of great potential in transdermal drug delivery systems.

In recent years, deep eutectic systems (DES) emerged as novel vehicles for facilitating the transdermal delivery of various drugs, including polysaccharides, proteins, insulin, vaccine, nanoparticles, and herb extracts. The objective of this study is to conduct a comprehensive review of the application of DES to transdermal drug delivery, based on previous work and the reported references. Following a brief overview, the roles of DES in TDDS, the modes of action, as well as the structure–activity relationship of DES are discussed. Particularly, the skin permeation of active macromolecules and rigid nanoparticles, which are the defining characteristics of DES, are extensively discussed. The objective is to provide a comprehensive understanding of the current investigation and development of DES-based transdermal delivery systems, as well as a framework for the construction of novel DES-TDDS in the future.