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Schematic illustration of siRNA-CPPs/NGR-TSL for specific siRNA delivery to tumor cells under dual stimulus of hyperthermia and intracellular redox environment. NGR-modified liposomes are retained in the tumor due to the active targeting effect by the NGR ligand. In the body circulation, as siRNA-CPPs were encapsulated in NGR-TSL, they can not penetrate into the normal cell membrane and be degraded by enzyme in the blood. However, upon heat-stimulus at the tumor site, siRNA-CPPs were released, the interaction of CPPs with the cell membrane is restored and mediated siRNA rapidly enter into the cells membrane and escape from the endosomal entrapment into the cytosol. At last, free siRNA was released from the CPPs via disulfide-bond broken under the stimulus of GSH in the cytosol and silenced c-myc gene over expressed in HT-1080 cells.Small interfering RNA (siRNA) offers a new and potential therapeutic strategy for tackling many diseases at the molecular level. Recently, cell-penetrating peptides (CPPs) conjugated with siRNA via disulfide-bonds (designated as siRNA-CPPs) were reported to form glutathione-sensitive carriers. However, non-cell specificity, CPPs degradation and the unwanted reduction of siRNA-CPPs before reaching the targeted tissue in vivo hampered the development of siRNA-CPPs. Herein, utilizing the dual stimulus of hyperthermia and the intracellular redox environment, we devised a thermosensitive liposome (TSL) containing an Asparagine-Glycine-Arginine (NGR) peptide and reducible siRNA-CPPs for tumor-specific siRNA transfection (siRNA-CPPs/NGR-TSL), in which siRNA-CPPs were “caged” in NGR-TSL to overcome their limitations in vivo. The functional nanocarrier possessed a small particle size of approximately 90 nm, a high drug encapsulation efficiency of approximately 86% and good serum stability. Both free siRNA-CPPs and siRNA-CPPs/NGR-TSL (preheated) silenced c-myc in human fibrosarcoma (HT-1080) cells in vitro. However, in an HT-1080 xenograft murine model, siRNA-CPPs/NGR-TSL with hyperthermia displayed superior in vivo antitumor efficacy (about 3-fold) and gene silencing efficiency (about 2-fold) compared with free siRNA-CPPs under hyperthermia. This study demonstrates that the constructed vesicle in combination with hyperthermia could greatly improve the in vivo stability of siRNA-CPPs and synergistically enhance its cancer therapy efficiency.