The discovery of RNA interference (RNAi) has opened a new strategy in cancer therapy, especially by silencing target genes. Pharmacologically it can be achieved by introducing of small (19–21 base pairs) dsRNA molecules known as small interfering RNA (siRNA) targeting interested genes. siRNA mediated gene has been widely investigated for its utility in treating various diseases including cancer. However, the systemic delivery of interested siRNA via non-viral methods remains a major challenge with large numbers of polymeric and liposomal systems being tested. The most effective methods involving cationic liposomes delivery to cells. Nonetheless, systemic delivery of siRNA via cationic lipid particles is often poor due to rapid uptake by reticuloendothelial organs, resulting in decreased delivery of these particles to the site of interest. Polyethylene glycol (PEG) has been used in siRNA-liposomes formulation to minimize reticuloendothelial uptake. Also, PEGylation permits the accumulation of the liposomes-loaded siRNA at the tumor sites with defective vasculatures such as enhanced permeability and retention phenomena. Thus, a simple method to prepare stable PEGylated siRNA-loaded lipid particles could provide better systemic delivery system in treating various cancers, including papillary thyroid carcinoma. Here we illustrate a simple protocol for the formulation of siRNA-loaded lipid particles by hydration of freeze-dried matrix (HFDM) method for effective delivery of target specific siRNA to papillary thyroid carcinoma cells.