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.

open-flow microperfusion, are time-consuming, cumbersome, patient-unfriendly, requiring medical expertise and specialized equipment. [2] Microneedles (MNs) have then been proposed for the extraction of skin ISF due to their minimally invasive and easy-to-administrated properties. [3,4,5] Hydrogel-based swellable MNs are especially attractive because of their simplicity, efficiency, and biocompatibility. Samant et al. recently showed that polyvinyl alcohol (PVA)-based hydrogel patch could collect ISF from ex vivo pig skin [4] {[(Samant, 2018 #7)]} while our group developed the methacrylated hyaluronic acid (MeHA)-based hydrogel patch for ISF extraction from mouse skin in vivo without external devices. [5] Although the results from both systems were exciting, they were limited to the sampling time for the collection of the sufficient volume of ISF (1-10 µL) and the additional steps for quantifying the biomarkers in ISF. Assuming that both aforementioned systems maintain their performance in human skin as those in pig/mouse skin, PVA patch with 100 MNs can only extract 0.3 µL ISF after 12 h, while MeHA patch with 100 MNs required 20 min to collect 2.5 µL ISF. 20 min collection time is acceptable for the examination of biomarkers like cancer biomarkers or cholesterol that are relatively stable during this collection period but is definitely too long for biomarkers like O 2 and glucose whose concentration Hydrogel microneedle patch enables the extraction of skin interstitial fluid (ISF) through in situ swelling in a minimally invasive manner without assistance of mechano-chemical peripherals. However, existing hydrogel microneedles require tens of minutes with multistep process to collect sufficient volume (1 mL) for effective analysis. This study introduces an osmolyte-powered hydrogel microneedle patch that can extract ISF three times faster than the existing platforms and provide in situ analysis of extracted biomarkers. The microneedle patch is composed of osmolytes (i.e., maltose) and hydrogel (i.e., methacrylated hyaluronic acid). During the extraction process, the osmolytes dissolve in the matrix and provide the osmotic pressure that increases the diffusion of ISF from skin to the hydrogel matrix. A patch with 100 microneedles can extract 7.90 µL of ISF from pig skin ex vivo and 3.82 µL of ISF from mouse skin in vivo within 3 min, whereas the control (i.e., hydrogel microneedle without osmolytes) requires >10 min to achieve similar results. The extracted ISF allows the quantification of biomarkers such as glucose and/or drugs such as insulin in vivo. Through the integration with the electronic glucose sensors, the whole system permits the direct and rapid analysis of the extracted glucose.

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This work reports a frozen spray-coating method for the fabrication of double-layered microneedles (MNs). Taking swellable methacrylated hyaluronic acid (MeHA)-derived MNs as the model, both hydrophobic molecules (Nile red, Cy5) and hydrophilic ones (FITC, FITC-Dextran, Insulin) can be homogeneously coated without impacting the mechanical properties of the original MeHA MNs. The prepared double-layered MNs can execute multiple roles. It is demonstrated that insulin-coated MeHA double-layered MNs allow the effective delivery of the insulin into circulation of mice for controlling the blood glucose level while they also permit the extraction of skin interstitial fluid for the timely analysis of the biomarker (glucose).

Development of siRNA-loaded mesoporous Silica nanoparticles coated with poly-l-lysine for enhanced transdermal drug delivery in skin cancer treatment.