Potential Enhancement of Topical Drug Delivery Using Grapefruit-derived Nanoparticles Modified Using TAT Peptide

Purpose: Plant-derived nanoparticles (PdNPs) have garnered increasing attention as versatile tools for nucleic acid delivery, and they have been investigated for the transdermal delivery of encapsulated nucleic acids. However, not all PdNPs have high skin penetration enhancement ability. Surface modification of PdNPs with cell penetration peptides (CPPs) can enable skin penetration, with the Tat-peptide selected as a suitable CPP. In the present study, the feasibility of enhancing skin penetration was evaluated using grapefruit-derived nanoparticles (GNPs) modified with stearylated Tat-peptide (STR-Tat). Methods: The surface modification of GNPs with STR-Tat was conducted using a simple mixing method of synthesized STR-Tat with GNPs. Changes in particle size and zeta-potential of STR-Tat-GNPs were measured. In addition, in vivo skin penetration experiments were conducted as well as investigating cellular uptake and cell toxicity to determine the effect of surface modification on the skin penetration ability of GNPs. Results: A positive zeta potential was observed for STR-Tat-GNPs, whereas GNPs had a negative zeta potential. In addition, increased cellular uptake was confirmed for STR-Tat-GNPs without extensive cell toxicity. DiI-derived fluorescence was observed in hair follicles and at deeper sites of the dermis when DiI-labelled STR-Tat-GNPs were applied on mouse back skin in in vivo conditions. Conclusion: A simple mixing procedure of STR-Tat enhanced the skin penetration ability of a lipophilic dye initially associated with GNPs without cellular toxicity. Therefore, this approach may be applicable for providing plant-derived particles, which are expected to be an effective vehicle for nucleic acid delivery with high skin penetration ability.