The ability of short-interfering RNA (siRNA) to silence the activity of specific genes has proved very useful in dissecting genetic function and holds promise as a novel molecular therapeutic approach to silence disease-causing genes. The therapeutic potential of siRNA-based therapeutics in cancer treatment has been increasingly recognized in vitro and in vivo. However, the main obstacle to achieving in vivo cancer gene silencing by siRNA technologies is the systemic delivery and the tumor selectivity. To realize the full potential of siRNA-based therapeutics, we propose to develop a “smart” anti-tumor siRNA-nanotherapeutics that is capable of tumor-targeted systemic delivery, molecular imaging, infrared-triggered release, and tumor cell killing. Our approach is based on the specially designed, optically responsive, and bio-compatible gold nanoshells (GNS) developed in the Halas laboratory at Rice University. These nanoparticles can be tuned to absorb light in the infrared region and the resulting local photothermal response can be used to trigger drug release from a carrier in the local vicinity of the nanoparticle. This GNS-siRNA nanotherapeutics will be evaluated for their tumor-selectivity mediated by the targeting ligand coated on the GNS surface, cellular uptakes and localization, infrared-controlled release, gene expression silence, and anticancer-therapeutic effects in human lung cancer cells in vitro and in animal models in Dr. Ji’s laboratory at the UT M.D. Anderson Cancer Center. If this approach is successful, this GNS-siRNA nano-therapeutic system will represent a major advancement in the siRNA delivery technology and it may have an immediate translational application for the systemic and tumor-targeted treatment for lung cancer and other human cancers.