In this study, polypeptide-based nanoparticles [constituted using poly(l-lysine) coupled with deoxycholic acid (DOCA) and conjugated with 2,3-dimethylmaleic acid (DMA)] have high tumor selectivity once electrostatically switched by the acidic milieu of solid tumors. These nanoparticles exhibited a significantly increased in vitro cellular uptake and high accumulation in the acidic tumor site in vivo. Consequently, Fe3O4-loaded nanoparticles enabled high contrast magnetic resonance (MR) imaging of the tumor in vivo.