Therapeutically potent macromolecular drugs have shown great promise for overcoming the limitations of small-molecule anti-cancer drugs.But tumor cell-selective intracellular delivery of the macromolecules remains a major hurdle for their successful clinical application.To overcome this challenge,we engineered a novel genetic fusion protein (F3-Gel) that composed of F3 peptide,a tumorhoming peptide,and gelonin,a plant-derived ribosome-inactivating protein (RIP),and then evaluated its anti-cancer activity in vitro and in vivo.The F3-Gel-encoding gene was synthesized by genetic recombination,and F3-Gel was successfully expressed in E coll.The anti-cancer activity of the produced F3-Gel was evaluated by various in vitro assays,which revealed that F3-Gel maintained equipotent protein synthesis inhibition activity (IC50=11 pmol/L) as unmodified gelonin (IC50=1O pmol/L).Furthermore,F3-Gel displayed enhanced cellular uptake into cancer cells (U87 MG,HeLa,LnCaP and 9L) than noncancerous cells (293 HEK and SVGp12).Compared with gelonin,F3-Gel exerted significantly higher cytotoxicity against these cancer cells.F3-Gel displayed significantly greater inhibition of protein translation in U87 MG cells:F3-Gel (0.5 μmol/L) was able to reduce the protein level to less than 50％,while gelonin (1 μmol/L) did not affect the intracellular protein level.In a U87 MG xenograft tumor-bearing mouse model,F3-Gel was accumulated in the tumor site at much higher levels and maintained for a prolonged time compared with gelonin.Administration of F3-Gel (0.5,0.75 mol/kg,iv) caused 36％ and 66％,respectively,inhibition of tumor growth in U87 MG xenograft mice,suggesting that it is a promising candidate drug for cancer treatment.Furthermore,this study demonstrates that fusion of F3 peptide to a potent macromolecule could provides an effective method for targeting tumors and eventually could improve their druggability.