Small interfering RNA (siRNA) is a promising tool for the treatment of skin disorders including skin squamous cell carcinoma (SCC). This article develops a topical formulation for the transdermal delivery of siRNA. The formulation is built on mesoporous silica nanoparticles (MSNPs) with a loading capacity of 1.4 μg of oligonucleotide per mg of MSNPs. Cell experiments are employed to study the functionality of the formulation including the cellular uptake, the qualitative and quantitative detection of specific gene biomarkers. The clinical potential of this system is examined by topically delivering siRNA targeting TGFβR-1 (TGFβR-1) to the SCC in a mouse xenograft model. In comparison to the controls, MSNPs containing TGFβR-1 siRNA show a 2-fold suppression of TGFβR-1.