Dissolvable Microneedle Administration Combined with Ultrasonic Cavitation Promotes Melanoma Penetrating Capability of Ce6

Purpose: Melanoma, a highly aggressive superficial malignancy with rising incidence and mortality, faces limited sonodynamic therapy (SDT) efficacy due to poor sonosensitizer accumulation and penetration. To overcome this, we employed chlorin e6 (Ce6), a high-ROS-yield sonosensitizer, and enhanced its tumor delivery using a synergistic microneedle (MN) and ultrasound (US) strategy.Methods: Using melanoma as an application scenario, a “stepwise drug delivery” system was developed. It consisted of dissolving MN encapsulating US-responsive nanoparticles (Ce6-PFP@PLGA, CPP) and termed CPP@MN. CPP@MN breaks through the stratum corneum to deliver CPP to tumors, followed by US-triggered cavitation that mediates perfluoropentane (PFP) phase transition to enhance the tumor-penetrating capability of chlorin e6 (Ce6). Delivery efficacy was validated using three experimental models: an in vitro agarose skin phantom, ex vivo pig skin, and in vivo tumors. Furthermore, the anti-tumor efficacy of US-combined CPP@MN was evaluated at the cellular level and in tumor-bearing mice.Results: According to the results, CPP@MN showed excellent transdermal performance, including rapid dissolution of sonosensitizer and sufficient mechanical strength. MN combined with US increased the tumor penetration depth of loading drug by 2.5– 4 times across all experimental models. Ultrasonic cavitation promotes nanoparticle-derived Ce6 release and deeper tumor diffusion, resulting in specific anti-tumor efficacy.Conclusion: This innovative “stepwise drug delivery” system addresses persistent challenges in superficial tumor SDT, including inadequate sonosensitizer aggregation and poor tissue penetration, while establishing a multifunctional platform for spatiotemporally controlled drug release that sequentially overcomes the skin biological barriers.