Melanoma, a highly aggressive and metastatic skin cancer, presents a significant therapeutic challenge. Current treatments often involve complex procedures and high costs. Wearable biopatches offer a promising alternative, delivering external stimulation to damage tumor cells. While self-powered electrical patches and hyperthermia-based patches exist, they often suffer from complex fabrication processes and high costs. This necessitates the development of a simple, multi-responsive, and wearable patch for effective melanoma treatment. Ionic gels, with their flexible nature and ability to incorporate electrolytes, are attractive candidates for such patches. Their inherent properties, such as high ionic conductivity, electrochemical and thermal stability, and antibacterial ability, are further enhanced by doping with photothermal agents. MXene, a 2D material with excellent electroconductivity and photothermal properties, is an ideal candidate for this purpose. Electrical stimulation (ES) is a non-invasive therapeutic modality that modulates cellular activity with minimal side effects. It has shown efficacy in regulating cell migration, proliferation, differentiation, and death, making it suitable for cancer therapy. Combining ES with photothermal therapy (PTT), which uses photosensitizers to convert light into heat for tumor destruction, offers a synergistic approach. Traditional photothermal materials, however, often lack good skin contact and real-time visual monitoring capabilities. The eT-patch addresses these limitations by utilizing a transparent ionic gel for real-time observation of the treatment process.

The literature review section highlights existing research on various self-powered electrical patches and hyperthermia-based approaches for skin tumor treatment. Several studies have explored the use of Joule heating and other stimulation methods for cancer therapy. However, limitations regarding complexity, cost, and ease of fabrication are identified. The advantages of ionic gels as flexible and biocompatible materials, along with the unique properties of MXene as a photothermal agent, are discussed in relation to existing literature on these materials' applications in biomedical engineering and cancer therapy. The existing literature also supports the use of electrical stimulation as an effective method to trigger cell death in cancer cells, with studies demonstrating its impact on apoptosis and other cellular processes. The combination of PTT and ES is proposed as a potentially superior approach compared to using either modality alone.

The study details the synthesis of the eT-patch, beginning with the preparation of MXene nanosheets (Ti3C2Tx) via etching Ti3AlC2 powder. The nanosheets' characteristics are examined using scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS), confirming their 2D layered structure and surface functional groups. UV-Vis absorption spectroscopy confirms its suitability for 808 nm laser irradiation. Biocompatibility is assessed using MTT assays. The eT-patch is fabricated via ultraviolet lamp polymerization of an ionic gel precursor solution containing MXene nanosheets. SEM, energy-dispersive spectroscopy (EDS), and elemental mapping confirm the uniform dispersion of MXene within the gel. Mechanical properties, including stress-strain curves and toughness, are evaluated. Photothermal conversion efficiency is determined, and thermal stability is tested under repeated 808 nm laser irradiation. Electrical conductivity is characterized through current-voltage curves and impedance measurements. A poly(acrylamide-co-acrylic acid) hydrogel doped with MXene serves as a control to highlight the advantages of the ionic gel patch. In vitro biocompatibility is assessed using MTT assays with B16F10 melanoma cells, evaluating the effects of both MXene and ionic gel extracts on cell viability. The effects of different electrical stimulation currents on B16F10 cell viability are also investigated using live/dead staining and MTT assays. The efficacy of photothermal treatment with various laser powers is determined. Finally, the combined effect of photothermal and electrical stimulation (PES) is evaluated using live/dead staining, RT-PCR to analyze gene expression related to apoptosis and pyroptosis, LDH release assays, ATP assays, bio-TEM, ROS detection, JC-1 assays for mitochondrial membrane potential, and γ-H2AX immunofluorescence staining to assess DNA damage. In vivo studies involve establishing a B16F10 melanoma-bearing C57BL/6J mouse model. Mice are treated with various methods (control, laser, PTT, ES, PES) for 10 min per treatment over two consecutive days, and tumor size is monitored. Tumor weight, relative tumor volume, and body weight are measured. H&E staining, Ki-67 staining, TUNEL staining, and GSDME and caspase-3 immunohistochemical staining are performed on tumor tissues. Histological analysis of major organs is conducted. Blood tests are performed to assess systemic toxicity.

The synthesized MXene nanosheets exhibited a 2D layered structure with a thickness of about 2 nm, confirming successful exfoliation. The MXene nanosheets showed a significant absorption peak at 768 nm, making them suitable for use with an 808 nm laser for PTT. The ionic gel patches doped with MXene exhibited improved mechanical properties, with increased elongation at break and toughness compared to pure ionic gel patches. The eT-patch displayed superior thermal stability, maintaining its photothermal conversion efficiency even after repeated laser irradiation. The eT-patch showed enhanced electrical conductivity compared to pure ionic gel patches. The in vitro studies showed that PES treatment significantly reduced B16F10 cell viability, inducing both apoptosis and pyroptosis. RT-PCR revealed increased expression of markers associated with pyroptosis (GSDME, Caspase-3, IL-1β) and apoptosis (Bax, c-Jun, Cyt-c) after PES treatment. LDH release assays confirmed enhanced pyroptosis, while ATP assays showed reduced ATP levels. Bio-TEM imaging demonstrated mitochondrial dysfunction. ROS levels and DNA damage were significantly higher after PES treatment compared to other treatment groups. In vivo studies showed a significant reduction in tumor size and weight in the PES group compared to other treatment groups. The PES treatment demonstrated high efficacy in suppressing tumor growth in the mouse model, with minimal impact on mouse body weight or major organ health. Histological examination revealed extensive tumor cell apoptosis and necrosis in the PES group. The study found no evidence of lung metastasis in any treatment group. The surrounding normal tissues showed minimal damage after treatment.

The results demonstrate the successful development and application of a novel eT-patch for efficient melanoma treatment. The synergistic combination of PTT and ES in the PES treatment resulted in significantly enhanced anti-tumor effects compared to either therapy alone. The superior performance of the eT-patch is attributed to the synergistic effects of MXene's photothermal properties and ES's ability to trigger pyroptosis and apoptosis. The transparent nature of the patch allows for real-time monitoring of treatment progress, minimizing the risk of tissue damage. The excellent biocompatibility and minimal systemic toxicity of the eT-patch make it a promising candidate for clinical translation.

This study successfully developed a wearable, dual-responsive eT-patch for effective melanoma treatment. The patch's transparency enables real-time monitoring of treatment effects. PES treatment triggered both apoptosis and pyroptosis in melanoma cells, leading to significant tumor suppression in vivo. The eT-patch exhibits high biosafety and stability. This work opens new avenues for exploring advanced patch materials for cancer treatment and expands the biomedical applications of ionic gels. Future research could focus on optimizing the patch's design, exploring different MXene compositions, and conducting larger-scale preclinical studies before clinical trials.

The study was conducted using a B16F10 mouse model, which might not fully represent the complexity of human melanoma. The long-term effects of the eT-patch on the surrounding normal tissues require further investigation. The optimal parameters for PES treatment might vary depending on tumor characteristics and individual patient responses. A larger sample size in animal studies would be needed to solidify the current findings.