Targeting Proteins in Nucleus through Dual-Regulatory Pathways Acting in Cytoplasm

Nuclear proteins have been regarded as attractive targets for exploiting therapeutic agents. However, those agents cannot efficiently pass through nuclear pores and it is also difficult to overcome the crowded nuclear environment to react with proteins. Herein, we propose a novel strategy acting in the cytoplasm to regulate nuclear proteins based on their signaling pathways, instead of directly entering into nuclei. A multifunctional complex PKK-TTP/hs carries human telomerase reverse transcriptase (hTERT) small interfering RNA (defined as hs) for gene silencing in the cytoplasm, which reduced the import of nuclear protein. At the same time, it could generate reactive oxygen species (ROS) under light irradiation, which raised the export of nuclear proteins by promoting proteins translocation. Through this dual-regulatory pathway, we successfully reduced nuclear protein (hTERT proteins) in vivo (42.3%). This work bypasses the challenge of directly entering into the nucleus and provides an effective strategy for regulating nuclear proteins.