Bioengineered protein nanocage by small heat shock proteins delivering mTERT siRNA for enhanced colorectal cancer suppression

The efficient delivery of small interfering RNA (siRNA) for target gene silencing holds great promise for cancer therapy. Protein nanocages have attracted considerable attention as ideal drug delivery systems because of their material-derived advantages and unique structural properties. However, most studies about siRNA delivery have not indicated the real role of protein nanocages in inhibiting tumor growth in vivo. Herein, we fabricated an efficient siRNA delivery system using a small heat shock protein (Hsp) nanocage decorated with Arg-Gly-Asp (RGD) and the transactivator of transcription (Tat) peptide. Hsp-Tat-RGD NC showed good cellular uptake and lysosomal escape in colorectal cancer cells. In addition, the nanocage could efficiently transfect siRNA into the cytoplasmic area of CT26 cells. Hsp-Tat-RGD NC delivering telomerase reverse transcriptase (TERT)-targeting siRNA could significantly downregulate TERT protein expression and trigger tumor cell apoptosis in vitro. More importantly, Hsp-Tat-RGD/siTERT complexes nearly completely inhibited the tumor growth after five times of treatment in mice bearing CT26 xenograft. Our results demonstrate the great potential of the Tat/RGD-decorated Hsp nanocage as a promising siRNA delivery platform for cancer therapy.