Noninvasive and Precise Transdermal Drug Delivery Using Spatiotemporally Responsive Lipid Vesicles in Conjunction with Ultrasound

Transdermal drug delivery (TDD) is influenced by the multiple anatomical layers of skin and various barriers, making the precise delivery of multiple drugs to specific spatial locations for optimal therapeutic efficacy a challenging prospect. This study proposes a strategy involving the use of spatiotemporally responsive lipid vesicles in conjunction with ultrasound (360 kHz, 1 W) for achieving noninvasive and precise TDD. The lipid vesicles prepared using microfluidic technology exhibited differences in particle size, loading capacity, and ultrasound responsiveness. Owing to variations in the vesicle mass, the distinct vesicle types exhibited considerable differences in their spatial distribution. Additionally, the vesicles showed remarkable differences in rupture times due to variations in their ultrasound responsiveness. In vitro and in vivo studies elucidated the mechanisms enabling precise regulation of the delivery sequence, penetration depth, and targeted structural layers of two drugs with similar molecular weights encapsulated in two distinct types of vesicles. As a proof of concept, the application of the spatiotemporally responsive vesicles in conjunction with ultrasound significantly enhanced healing in a hamster model of oral mucositis, achieving a wound closure rate of 91.42% ± 14.77% on day 8 post-treatment compared to 67.27% ± 12.85% and 80.00% ± 14.14% achieved upon blank control and treatment with the drug-loaded vesicles but without ultrasound exposure, respectively. These findings support the potential of applying this strategy to achieve transdermal delivery of multiple drugs in a noninvasive and precise manner.