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.

Tailored metal nanoclusters have been actively developed to manipulate light at the subwavelength scale for nanophotonic applications. Nevertheless, precise arrangement of molecules in a hot spot with fixed numbers and positions remains challenging. Here, we show that DNA origami metamolecules with Fano resonances (DMFR) can precisely localize single dye molecules and produce quantified surface-enhanced Raman scattering (SERS) responses. To enable tailored plasmonic permutations, we develop a general and programmable method for anchoring a set of large gold nanoparticles (L-AuNPs) on prescribed n-tuple docking sites of super-origami DNA frameworks. A tetrameric nanocluster with four spatially organized 80-nm L-AuNPs exhibits peak-and-dip Fano characteristics. The drastic enhancement at the wavelength of the Fano minimum allows the collection of prominent SERS spectrum for even a single dye molecule. We expect that DMFR provides physical insights into single-molecule SERS and opens new opportunities for developing plasmonic nanodevices for ultrasensitive sensing, nanocircuits, and nanophotonic lasers.