Cancer targeting delivery and controlled release of metal complexes may offer a new approach to improve their anticancer efficacy with eliminated systemic toxicities. Herein, a biotin-conjugated tri-block polymer delivery system was designed and used as a carrier of potent ruthenium polypyridyl (RuPOP) complexes to achieve superior biocompatibility, higher water solubility and cancer-targeting ability. Biotin was used as a targeting molecule to enhance the cellular uptake and retention of RuPOP in diverse carcinoma cells. Furthermore, the nanosystem (Bio-PLGA@Ru) was efficiently internalized by cancer cells by the lipid raft-mediated endocytosis pathway, triggered ROS overproduction and activated p53-mediated apoptosis in cancer cells. Moreover, the nanosystem effectively accumulated in tumor tissue and alleviated the damage of the metal complex to the organs. Taken together, this study demonstrates a smart strategy for the fabrication of a biocompatible and cancer-targeted PLGA-based copolymer nanosystem to achieve superior tumor cell localization and anticancer ability with eliminated systemic toxicities.