In silico optimized cell-penetrating peptides achieve transdermal siRNA delivery and regulate inflammatory...

To enable Small Interfering RNA (siRNA) transdermal delivery, we use computational modeling to predict key properties of four cationic peptide carriers. These parameters can be utilized for the prediction of peptide carrier diffusion within the stratum corneum, thereby facilitating the screening of carriers with transdermal delivery capabilities. We take this opportunity to examine the discrepancy between computer-simulated transdermal vehicle functions and actual therapeutic efficacy. We validate the therapeutic efficacy of four peptide carriers by employing both human cell-derived 3D skin models and a murine psoriasis model. To advance clinical applications, we developed a skin-adhesive spray that contains peptide carriers loaded with ADAM17-targeting siRNA. Following penetration into the dermis, the siRNA-loaded carriers are internalized by immune cells, downregulating a disintegrin and metalloproteinase 17 (ADAM17) protein expression. This consequently suppresses Tumor Necrosis Factor-α (TNF-α)-mediated inflammatory responses and ameliorates psoriatic pathology. Finally, by employing multiplex immunofluorescence imaging to visualize the spatial proximity between epithelial and immune cells, we elucidate their functional cross-talk within the tissue microenvironment. The findings demonstrate that our computer-optimized peptide carrier achieves transdermal siRNA delivery and reprograms the psoriasis-associated inflammatory microenvironment.