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.