Self-assembled nanovesicles integrated patch mediated transdermal delivery of Chinese medicinal formula alleviates insomnia with high safety

Insomnia, a prevalent neurological disease, is characterized by neurotransmitter disorder, inflammation and oxidative stress. Current treatments are often limited in efficacy due to their single-target regulatory mechanisms. YiNianJin (YNJ) is a classical formula that employs multiple therapeutic effects in treating insomnia. However, conventional oral delivery of YNJ formula is challenged by notable limitations, including Hg 2+ accumulation released from cinnabar, limited bioavailability of active constituents, that resulted in both of the toxicity issue and limited therapeutic efficacy. To address these multiple obstacles, we developed a peptide self-assembled penetrating nanovesicles integrated within a controlled releasing matrix, forming into YNJ patch (YNJP). Cinnabar is encapsulated within nanovesicles functionalized with cell-penetrating (YGRKKRRQRRR, TAT) and intestinal wall-penetrating (CSKSSDYQC, CSK) peptides, forming TAT/CSK-cinnabar vesicles (TCCV), and integrated into a controlled-release polymeric matrix, loaded with other herbal components, forming into a hybrid patch. YNJP is shown to significantly enhance the sequential penetration of cinnabar across the stratum corneum (SC), abdominal fat, and small intestinal wall, along with the obvious efficacy in the transdermal delivery of other herbal components. Compared with the conventional oral delivery of YNJ, YNJP significantly reduced the Hg 2+ accumulation in major organs by 58.3%–85.8%. In addition to inhibit the inflammation and oxidative stress to relieve insomnia, YNJP can also restore the brain-gut axis mediated serotonin (5-HT) release and 5-HT1A receptors (5-HT1AR) activation, representing a safe and innovative transdermal delivery platform for Chinese formulae containing both multiple homogenous components and toxic compound, as well as offering a new Chinese medicine scheme for the treatment of complex disorders such as insomnia with high efficiency and biosafety.