DNA nanostructures are promising drug carriers with their intrinsic biocompatibility, uniformity and versatility. However, rapid serum disintegration leads to low bioavailability at targeted sites following systemic administration, hindering their biomedical applications. Here we demonstrate transdermal delivery of framework nucleic acids (FNAs) through topical applications. By designing FNAs with distinct shapes and sizes, we interrogate their penetration on mice and human skin explant. Skin histology reveals size-dependent penetration, with FNAs ≤75 nm effectively reaching dermis layer. 17 nm-tetrahedral FNAs show greatest penetration to 350 µm from skin periphery. Importantly, structural integrity is maintained during the skin penetration. Employing a mouse melanoma model, topical application of doxorubicin-loaded FNAs accommodates ≥2-fold improvement in drug accumulation and tumor inhibition relative to topically-applied free doxorubicin, or doxorubicin loaded in liposomes and polymeric nanoparticles. Programmable penetration with minimal systemic biodistribution underlines FNA potential as localized transdermal drug delivery carriers.

DNA纳米结构因其固有的生物相容性、均匀性和多功能性而成为有前途的药物载体。然而，快速的血清崩解导致全身给药后目标部位的生物利用度较低，阻碍了其生物医学应用。在这里，我们展示了通过局部应用的框架核酸（FNA）的透皮递送。通过设计具有不同形状和尺寸的 FNA，我们研究了它们对小鼠和人类皮肤外植体的渗透性。皮肤组织学揭示了尺寸依赖性渗透，FNA ≤75 nm 可有效到达真皮层。17 nm 四面体 FNA 显示出从皮肤周边至 350 µm 的最大穿透力。重要的是，在皮肤渗透过程中保持结构完整性。采用小鼠黑色素瘤模型，相对于局部应用的游离阿霉素或脂质体和聚合物纳米颗粒中负载的阿霉素，局部应用负载阿霉素的 FNA 可将药物蓄积和肿瘤抑制改善 ≥2 倍。可编程渗透和最小的全身生物分布凸显了 FNA 作为局部透皮药物递送载体的潜力。