Tetrahedral framework nucleic acids carrying tranexamic acid to alleviate ultraviolet B-induced skin pigmentation

Hyperpigmentation disorders such as melasma require topical therapies that are both effective and well tolerated, yet many current depigmenting agents are limited by irritation or inconsistent efficacy. Tranexamic acid (TXA) is a clinically used small molecule with emerging anti-pigmentation utility, but its topical performance is often constrained by insufficient penetration and limited cellular access. In this work, we engineered a tetrahedral framework nucleic acid (tFNA)-enabled TXA formulation (tFNAs-TXA) to enhance topical delivery and anti-melanogenic activity. tFNAs-TXA was successfully constructed with preserved nanostructure, physicochemical stability, and efficient cellular internalization. Functionally, tFNAs-TXA significantly attenuated α-MSH-induced melanogenesis in B16 cells without overt cytotoxicity and downregulated the cAMP-p-CREB-MITF-TYR signaling cascade at both protein and mRNA levels. In a UVB-induced mouse model, topical tFNAs-TXA markedly reduced dorsal pigmentation and mitigated UVB-associated histopathological changes, including melanin deposition, collagen disorganization, and epidermal hyperplasia, achieving depigmenting efficacy with better gross tolerability. Together, these findings establish tFNAs-TXA as a concise, non-invasive delivery strategy that potentiates TXA for safer and more effective management of UV-related hyperpigmentation.