Transdermal InsulinDelivery for Type 1 Diabetes UsingReverse Electrodialysis and Ionic Liquid Technology Based on a Size-DependentProtein Delivery Study

Transdermal or topical skin delivery of protein therapeutics is currently limited due to the large molecular size of proteins and the dense structure of the skin. Although some nanoparticles and enhancers have been used to increase skin penetration and protein stability, few studies have examined the effect of protein size or the combination of enhancers on skin penetration. Here, we introduce Polycaprolactone (PCL) and Pluronic F-127-based polymeric nanoparticles (PNPs) to load different-sized proteins, including insulin (INS), trypsin inhibitor (TI), horseradish peroxidase (HRP), bovine serum albumin (BSA), and diamine oxidase (DAO). Utilizing a reverse electrodialysis (RED) battery and an ionic liquid (IL) system, we facilitated the delivery of protein-loaded PNPs (Protein_PNPs) up to depths of approximately 290 μm for INS and 153 μm for DAO noninvasively. When applied to the in vivo skin of type 1 diabetes-induced mice, the INS-loaded PNP (INS_PNP) was delivered transdermally with the IL+RED system, resulting in a normoglycemic state for up to 3 h. Our findings suggest that the IL+RED-assisted PNP skin protein delivery system holds promise for transdermal applications in protein therapeutics.