Co-delivery of gene and drug for synergistic therapy has provided a promising strategy to cure devastating diseases. The use of genomic predictors of response to cisplatin and pemetrexed can be incorporated into strategies to optimize therapy for advanced solid tumors. Here, a positive feedback strategy was utilized to amplify the concentration of intracellular reactive oxygen species (ROS) and a ROS-triggered self-accelerating drug release nanosystem (defined as T/D@RSMSNs) was demonstrated for enhanced tumor chemotherapy. It was found that in human breast cancer (MCF-7) cells, T/D@RSMSNs could not only release DOX and a-TOS initiatively, but also lead to increased concentration of intracellular ROS, which could be used as new trigger to cut away TK linkage and then in turn facilitate the further release of DOX for enhanced chemotherapy. Standard treatment for advanced non–small-cell lung cancer (NSCLC) includes the use of a platinum-based chemotherapy regimen. This novel ROS triggered self-accelerating drug release nanosystem with remarkably improved therapeutic effects could provide a general strategy to branch out the applications of existing ROS-responsive drug delivery systems (DDSs).