Topical Administration of Melatonin-Loaded Extracellular Vesicle-Mimetic Nanovesicles Improves 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis

Atopic dermatitis (AD) is caused by multiple factors that trigger chronic skin inflammation, including a defective skin barrier, immune cell activation, and microbial exposure. Although melatonin has an excellent biosafety profile and a potential to treat AD, there is limited clinical evidence from controlled trials that support the use of melatonin as an AD treatment. The delivery of melatonin via the transdermal delivery system is also a challenge in designing melatonin-based AD treatments. In this study, we generated melatonin-loaded extracellular vesicle-mimetic nanoparticles ((Mela)NVs) to improve the transdermal delivery of melatonin and to evaluate their therapeutic potential in AD. The (Mela)NVs were spherical nanoparticles with an average size of 100 nm, which is the optimal size for the transdermal delivery of drugs. (Mela)NVs showed anti-inflammatory effects by suppressing the release of TNF-alpha and beta-hexosaminidase in LPS-treated RAW264.7 cells and compound 48/80-treated RBL-2H3 cells, respectively. (Mela)NVs showed a superior suppressive effect compared to an equivalent concentration of free melatonin. Treating a 2,4-dinitrofluorobenzene (DNCB)-induced AD-like mouse model with (Mela)NVs improved AD by suppressing local inflammation, mast cell infiltration, and fibrosis. In addition, (Mela)NVs effectively suppressed serum IgE levels and regulated serum IFN-gamma and IL-4 levels. Taken together, these results suggest that (Mela)NVs are novel and efficient transdermal delivery systems of melatonin and that (Mela)NVs can be used as a treatment to improve AD.