Cryo-microneedle enabled transdermal delivery of two-dimensional Cu(Ⅱ)-TCPP nanomaterials for synergistic photodynamic-chemodynamic anti-tumor therapy

Photodynamic therapy (PDT) with photosensitizers (PSs) represents an innovative and advantageous approach to systematic superficial oncological treatment. However, the difficulties in precise and fast enrichment of PSs around the tumor site significantly limit the therapeutical efficacy for melanoma treatment. To address this, in this study, we utilized cryo-microneedles (CryoMNs) to facilitate the transdermal delivery of ultrathin two-dimensional Cu(Ⅱ)-TCPP as PSs nanomedicine. The CryoMN patches composed of frozen hyaluronic acid hydrogel penetrate the skin barrier and rapidly melt without creating many residual materials, enabling precise and biocompatible delivery of Cu(Ⅱ)-TCPP to the tumor site. The transdermally delivered Cu(Ⅱ)-TCPP nanosheets release Cu²⁺ ions and TCPP under the stimulation of the intratumoral microenvironment (characterized by low pH and high glutathione (GSH) content). The Cu²⁺ ions deplete excess GSH, subsequently triggering a Fenton-like reaction to generate hydroxyl radicals (·OH). Concurrently, TCPP produces singlet oxygen (¹O₂) under laser irradiation, thereby synergistically generating a higher concentration of toxic reactive oxygen species (ROS) for enhanced tumor therapy. By such a mechanism, the Cu(Ⅱ)-TCPP nanomedicine enhances ROS generation within the tumor, leading to tumor-specific oxidative damage and improved therapeutic outcomes through the synergistic effect. Both In-Vitro and In-Vivo experiments have demonstrated the effectiveness of CryoMN treatment and the synergistic benefits of chemodynamic therapy (CDT) and PDT. This approach targets the unique redox characteristics of the tumor microenvironment, producing highly toxic ROS and ultimately inducing tumor apoptosis. The results demonstrate that the delivery of nanomaterials via CryoMNs significantly inhibits melanoma, achieving an approximate tumor inhibition rate of 83%. This approach presents an effective and promising therapeutic strategy for future melanoma treatment.