α-Helical cell-penetrating peptide-mediated nasal delivery of resveratrol for inhibition of epithelial-to-mesenchymal transition

In the present study, we examined the potential of cell-penetrating peptide (CPP)-based intranasal drug delivery for the treatment of localized nasal diseases. Many charged or non-hydrophobic drugs have difficulty penetrating into the nasal epithelium due to intrinsic membrane impermeability and rapid mucociliary clearance in the nasal cavity. To treat chronic rhinosinusitis with nasal polyps (CRSwNP), one of the most common localized nasal diseases, we conjugated resveratrol (RSV) to an amphiphilic α-helical leucine (L)- and lysine (K)-rich CPP (LK) and intranasally delivered it to the interior of nasal epithelial cells for inhibiting epithelial-to-mesenchymal transition (EMT) caused by hypoxia-inducible factor 1α. The RSV-LK conjugate could penetrate into the nasal epithelium and efficiently inhibit EMT, nasal polyp formation, epithelial disruption, and related inflammation in an eosinophilic CRSwNP mouse model, at 10-fold lower doses and with 3-fold less frequent administration than free RSV. Due to the rapid penetration into the nasal epithelium and the therapeutic effect of the RSV-LK conjugate at much lower doses than free RSV, this CPP-based delivery system, with the ability to overcome the tight nasal epithelial barrier, may provide a new strategy for the treatment of localized nasal diseases without the systemic side effects of cargo drugs.