Targeted melanoma therapy: High-efficiency siRNA delivery with R8-PEI dissolvable microneedles

Cutaneous melanoma, characterized by its high malignancy and propensity for early metastasis, has become one of the most lethal forms of skin cancer. RNA interference (RNAi) presents a promising therapeutic strategy for melanoma by using small interfering RNAs (siRNAs) to silence gene expression. However, the clinical application of RNAi is hindered by challenges associated with siRNA delivery, including degradation by nucleases, limited cellular uptake, and the barrier of the stratum corneum. In this study, we developed a carrier system comprising of polyethyleneimine (PEI) modified with octamer arginine (R8), a cell-penetrating peptide, and utilized this modified PEI to fabricate dissolvable microneedles loaded with siRNA (siRNA@R8-PEI/DMNs).The siRNA@R8-PEI/DMNs exhibited an excellent overall appearance, featuring a flat backing layer and a needle content of (93.92 ± 4.23)%. The microneedles demonstrated robust mechanical strength,with an overall force of (62.13 ± 8.93) N and a tip strength of (1.69 ± 0.37) N, facilitating effective penetration through the Parafilm®M membrane to a depth of approximately 380 μm. In vitro puncture tests on rat skin revealed a puncture rate exceeding 80%, indicating the system's strong capability to penetrate the skin. In vitro cellular experiments demonstrated that siRNA@R8-PEI effectively inhibited the proliferation of A375 cells by approximately 90% in a concentration-dependent manner. Additionally, the 24-hour cell migration rate was reduced to approximately 20%, and the gene silencing efficiency reached up to about 74%. In vivo studies further confirmed the therapeutic potential of siRNA@R8-PEI/DMNs, with a volumetric tumor inhibition rate of about 67%, inducing tumor cell apoptosis and reducing BRAF expression.siRNA@R8-PEI/DMNs offer a promising transdermal siRNA delivery system for cutaneous melanoma therapy, potentially providing novel insights into the development of safe and efficient transdermal siRNA delivery vectors. This study lays the groundwork for further exploration of RNAi-based therapeutics in dermatological oncology.