Mesoporous silica nanoparticles (MSNPs) have garnered a great deal of attention as potential carriers for therapeutic payloads. However, achieving triggered drug release from MSNPs in vivo has been challenging. Here, we describe the synthesis of stimulus-responsive polymer-coated MSNPs and the loading of therapeutics into both the core and shell domains. We characterize MSNP drug-eluting properties in vitro and demonstrate that the polymer-coated MSNPs release doxorubicin in response to proteases present at a tumor site in vivo, resulting in cellular apoptosis. These results demonstrate the utility of polymer-coated nanoparticles in specifically delivering an antitumor payload.