Enhanced cellular and transdermal delivery of the modified chromatin using gH625 cell-penetrating peptide

Development of a transdermal drug delivery system must overcome the limited efficacy and reliability of current skin penetration methods. This study examined whether synthetic chromatin conjugated with the cell-penetrating peptide gH625 could traverse the epidermal barrier while maintaining cargo bioactivity. gH625-linked histone H2A assembled into chromatin was used to deliver DNA and peptides without penetration enhancers. gH625-chromatin increased cellular penetration by 150% compared with wild-type chromatin. Ex vivo porcine and in vivo mouse skin models demonstrated enhanced penetration depth up to 242 μm within 24 h, with signals confined to the dermis, indicating safe localized delivery. Epidermal growth factor (EGF) displayed at the histone H2B C-terminus maintained activity equivalent to free EGF, promoting cell growth, elevated COL1A1 secretion, and accelerated wound closure. These findings establish a chromatin-based nanoplatform for non-invasive transdermal delivery of bioactive macromolecules, filling a key gap in skin-targeted biotherapeutic delivery.