We prepare various protein-derived amphiphilic polymers. By modifying the polypeptide backbone with a few (58) hydrophilic or lipophilic substituents, we are able to switch the hydrophobicity of the polymer and control the formation of stable nano-sized micelles. In the hydrophobic interior of these micelles, ethynyl groups are introduced to provide a nanoreactor environment for click reactions with lipophilic cargo molecules, such as 3-azidocoumarin, a hydrophobic fluorophore, and the anti-cancer drug doxorubicin. These protein-derived amphiphilic polymers reported herein offer a promising potential to design a delivery platform for biomedical applications.