Oxaliplatin is a promising antitumor drug, but its effectiveness is limited by its side effects in vivo. In this study, we introduced an Oxaliplatin prodrug (Oxa(IV)) self-controlled release strategy, in which Oxa(IV) is encapsulated by TPGS functionalized mesoporous silica nanoparticles (MSNs), and its release is controlled by biological stimuli, such as acidic environments in tumor tissue and high concentrations of reductants in cancer cells. Despite the lack of auxiliary "gatekeepers" to MSNs, this simplified model of Oxa(IV)-MSNs-TPGS could fine-tune the movements of the drug release. Furthermore, we utilized a pro drug approach to avoid the side effects of Oxaliplatin, and we used TPGS groups to reduce multidrug resistance (MDR). Finally, the toxicity of Oxa(IV)-MSNs-TPGS to a human lung adenocarcinoma cell line (A549) in vitro was significantly lower than that of Oxaliplatin. This model demonstrates the considerable potential of a simple self-controlled release system with multiple functions. (C) 2018 Elsevier Inc. All rights reserved.