Microneedle-mediated multifunctional nano-transdermal therapy system for in situ synergistic treatment of melanoma

Abstract

Traditional drug delivery methods and treatments often lack efficacy in eradicating melanoma and can cause significant toxicity to healthy tissues. Combining microneedle (MN)-based transdermal drug delivery (TDD) with in situ synergistic therapy is crucial for overcoming these challenges. Thus, a novel multifunctional nano-TDD system was developed by integrating polyvinyl alcohol (PVA) MN with hyaluronic acid (HA)-functionalized calcium peroxide/copper peroxide @ zeolitic imidazolate framework (CaO₂/CuO₂@ZIF-8) nanocapsule co-loaded with 1-methyltryptophan (1-MT) and disulfiram (DSF). Nanomedicines reach deeper skin layers via MNs and targeted to the melanoma site by HA. Subsequently, ZIF-8 protective layer releases 1-MT and DSF in response to the acidic tumor microenvironment. The exposed CaO₂/CuO₂ nanoparticles decompose into Cu²⁺, Ca²⁺ and hydrogen peroxide (H₂O₂). Cu²⁺ catalyzes the generation of hydroxyl radical (•OH) from H₂O₂ to turn on chemodynamic therapy (CDT), and the efficiency of •OH generation can be further enhanced by depleting glutathione (GSH). Benefiting from the in-situ chelation reaction of DSF with Cu²⁺, CuET chemotherapy drugs with strong toxicity are generated. In addition, the produced Cu⁺ can further enhance the efficacy of CDT. The massive influx of Ca²⁺ exacerbates the damage to mitochondria. Ultimately, combining 1-MT to reverse the tumor's immunosuppressive microenvironment with chemotherapy and CDT-induced immunogenic cell death offers a promising and safe strategy for melanoma treatment.