Tetrahedral Framework Nucleic Acids as Thermal Loading Nanocarriers for Enhanced Inhibition of Melanin Synthesis

This study aimed to address the limitations of α-arbutin (α-Arb) in transdermal delivery and melanin inhibition by developing a tetrahedral framework nucleic acid (tFNA)-based nanocarrier (tFNA@α-Arb). Unlike conventional carriers, tFNA was chosen for its unique tetrahedral structure and nucleic-acid-derived biocompatibility, which enables superior skin penetration. A first-reported thermal loading method for nucleic acids was applied to encapsulate α-Arb, significantly enhancing the loading efficiency from 60.83% to 76.85% without compromising drug activity. Subsequent transdermal experiments demonstrated that tFNA could deposit in the epidermis and accumulate within the skin. Zebrafish experiments further validated the excellent transdermal properties and safety profile of tFNA@α-Arb, which resulted in an effective melanin reduction with an inhibition rate of 95.65%. Mechanistically, tFNA@α-Arb specifically downregulated melanin-synthesis-related genes (validated by RT-qPCR). In C57BL/6J mice, it showed more pronounced melanin reduction, confirming the synergistic effect of tFNA's delivery capability and α-Arb's activity. This study presents a tFNA-based platform that innovates both carrier design and loading strategy, offering a transformative solution for enhancing α-Arb's efficacy in melanin inhibition.