Ionic liquid-based transdermal drug delivery systems for biopharmaceuticals

The non-invasive transdermal delivery of biopharmaceuticals, including proteins, peptides, and nucleic acids, remains a considerable challenge because of the formidable barrier function of the stratum corneum. Ionic liquids (ILs) composed of tunable cations and anions have emerged as useful multifunctional materials in transdermal drug delivery systems (TDDS) because of their excellent physicochemical properties. By acting simultaneously as solvents and permeation enhancers, ILs can considerably improve the solubility and stability of labile biomolecules and facilitate their transport across the skin. Recent studies have demonstrated the successful integration of ILs into nanocarrier systems, including ethosomes, transethosomes, IL-in-oil micro-/nano-emulsion formulations, and solid-in-oil dispersions, enabling the effective transdermal delivery of insulin, siRNA, mRNA, and other biologics. Compared with conventional solvent-based transdermal systems, biocompatible IL-based formulations can confer high stability and enhanced drug bioavailability. This review surveys the most recent advances in IL-TDDS, with particular focus on lipid- and choline-derived IL-enabled TDDS that have demonstrated prolonged glycemic control in diabetic models and potent anti-tumor responses in nucleic-acid immunotherapy.