Efficient Transdermal Delivery of DNA Nanostructures Alleviates Atopic Dermatitis Symptoms in NC/Nga Mice

DNA nanostructures have been widely studied in biomedical research contributing to targeted treatment of chronic diseases. The immunostimulatory X_L-DNA nanostructures of X-shaped oligodeoxynucleotides complex are previously reported, activating toll-like receptor9 in dendritic cells. This study examines whether the X_L-DNA could be therapeutically applied to treat immune diseases such as atopic dermatitis. To optimize topical delivery, liposome-encapsulated X_L-DNA (Lipo-X_L-DNA) is generated using emulsion transfer method with lipid layers composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol), and cholesterol. Size distribution of Lipo-X_L-DNA ranges around 90–160 nm with mean diameter of 115.44 ± 18.72 nm. The morphology is confirmed by transmission electron microscope. Zeta potential is −28.59 mV. Confocal microscopy shows that Lipo-X_L-DNA is efficiently delivered into epidermis and dermis. Topical application of Lipo-X_L-DNA effectively alleviates atopic dermatitis symptoms in mice, as shown by dermatitis score, histological evaluation, and serum immunoglobulin E levels. RNA-seq analysis confirms that Lipo-X_L-DNA reduces pro-inflammatory products, but increases epidermal barrier homeostasis factors in atopic dermatitis lesions. Lipo-X_L-DNA orchestrates immune balance by downregulating Th2 immunity, but upregulating Th1 immunity. Collectively, liposome encapsulation enables efficient transdermal delivery of X_L-DNA, for an effective treatment of atopic dermatitis in mice. The results provide a promising therapeutic strategy using X_L-DNA nanostructures to treat immune-compromised diseases.