pH/reduction dual-triggered chicken-feather-keratin-based prodrug nanoparticles (C-PK/-SS-Hy-D NPs) were designed via a facile one-pot oxidation coupling reaction between the thiol-functional acid-labile prodrug M-Hy-D and the PEGylated keratin (PK) graft copolymer, for tumor intracellular doxorubicin (DOX) delivery. Due to the encapsulation of the pH and the reduction of the dual-responsive small prodrug D-Hy-SS-Hy-D, a high drug content of 45.8% was obtained in the proposed prodrug nanoparticles. They exhibited excellent pH and reduction of dual-triggered drug release, with cumulative drug release of 88.6% within 51 h in the simulated tumor intracellular microenvironment, while the premature drug leakage was only 13.7% in the simulated normal physiological medium. The in vitro experiments revealed the enhanced antitumor efficacy of the C-PK/-SS-Hy-D NPs than the free DOX at a higher dosage of >10 mu g/mL.