The specific down-regulation triggered through interference RNA (RNAi) provides a means to determine the gene functions and their contributions in an altered phenotype. In this way, high throughput screening (HTS) has emerged as a potent automated tool to study a large number of genes for identification of new biomarkers and therapeutic targets. However, the siRNA-mediated gene knock down requires that siRNA can reach cytoplasm compartment where RNAi occurs. Unfortunately, the siRNA is relatively vulnerable in the extracellular environment due to the presence of degradation enzymes and its high molecular weight associated to its anionic charge limit considerably its cell incorporation across the plasma membrane. Thereby, HTS requires generic carriers with highly efficient siRNA transfection. To overcome these obstacles, multifunctional nanoparticles comprising an imaging contrast agent are emerging as an original and promising approach in the improved, controlled and monitored delivery of siRNA.