A two-stage transdermal drug delivery system comprising sono-phase-change transfersomes for non-invasive deep dermal delivery.

Non-invasive deep transdermal drug delivery is required for conditions such as keloids. However, the skin's stratum corneum barrier is the primary obstacle for transdermal drug delivery methods. Most energy sources and operational controls are located externally, making it difficult to regulate the deep delivery of a drug once it has penetrated the stratum corneum barrier. Additionally, some transdermal administration methods that provide an internal energy source are frequently invasive and can cause damage. Therefore, achieving non-invasive drug delivery to the deep dermis for such conditions is challenging. Here, we propose sono-phase-change transfersomes (SPCTs) that stably encapsulate perfluoro-n-pentane within transfersomes. These SPCTs, combined with low-frequency and low-intensity ultrasound (LFLIU), are designed to create a two-stage transdermal drug delivery system that integrates passive and active penetration. In the first stage, the deformability of SPCTs enables them to stably and passively penetrate the epidermis. In the second stage, SPCTs undergo a phase change when ultrasound irradiation is applied, transforming into microbubbles. As the microbubbles penetrate deeper, they gradually expand, rupture, and release their encapsulated substances, providing supplementary energy from within to achieve active penetration. Both in vitro and in vivo experiments revealed a significant increase in the efficiency, depth, quantity, and distribution range of the contents entering the dermis. In addition, the SPCTs combined with the ultrasound group in the keloid nude mouse model exhibited the fastest keloid volume reduction, with various indicators demonstrating that its therapeutic effect was significantly better than that of the other control groups. These findings indicate that this two-stage transdermal drug delivery system can non-invasively and safely achieve deeper and higher-dose dermal administration, offering a new strategy for treating diseases such as keloid.