Protein-based drug delivery system has been extensively investigated as a safety system. Especially, ferritin nanocage from human origin has been shown no toxicity as using biomaterials. However, because protein generally has its native property related to sophisticated 3D structure, it is very difficult to modify its function as suitable for delivery system without changing outer morphology related to the safety problem. In this paper, we proposed new pH-responsive ferritin delivery carrier through 4-fold channel engineering technics with minimum morphological changes. With changing the 4-fold channel, ferritins have pH-dependent stabilities and unique drug uptake properties. Owing to new function of pH-responsive drug release from 4-fold engineered ferritin, it showed more effective anticancer effects and will be expected to approach new protein-based delivery system methods.