We have designed clathrin-like triskelion molecules with enzyme-responsive peptide units, Fmoc-Phe-Tyr-phosphate. At physiological pH, these three-legged molecules can self-assemble into spherical nanocages in the presence of phosphatase. The dimension and hollow spherical structure are characterized by dynamic light scattering and transmission electron microscopy. The ability to use enzymatic trigger for smart release is assessed. The potential to develop the new nanocages as drug delivery vehicles are further evaluated by measuring the encapsulation efficiency and release profile of model drug compounds.