lThe development of stimuli-responsive, nano-scale therapeutics that selectively target and attack tumors is a major research focus in cancer nanotechnology. A potent therapeutic option is to directly arming the cancer cells with apoptotic-inducing proteins that are not affected by tumoral anti-apoptotic maneuvers. The avian virus-derived apoptin forms a high-molecular weight protein complex that selectively accumulates in the nucleus of cancer cell to induce apoptotic cell death. To achieve the efficient intracellular delivery of this tumor-selective protein in functional form, we synthesized degradable, sub-100 nm, core shell protein nanocapsules containing the 2.4 MDa apoptin complexes. Recombinant apoptin is reversibly encapsulated in a positively charged, water soluble polymer shell and is released in native form in response to reducing conditions such as the cytoplasm. As characterized by confocal microscopy, the nanocapsules are efficiently internalized by mammalian cells tines, with accumulation of rhodamine-labeled apoptin in the nuclei of cancer cells only. Intracellularly released apoptin induced tumor-specific apoptosis in several cancer cell lines and inhibited tumor growth in vivo, demonstrating the potential of this polymer protein combination as an anticancer therapeutic. (C) 2013 Elsevier Ltd. All rights reserved.