Chemodynamic　therapy　(CDT)　utilizes　iron-initiated　Fenton　chemistry　to　destroy　tumor　cells　by　converting　endogenous　H2O2　into　the　highly　toxic　hydroxyl　radical　(.OH).　There　is　a　paucity　of　Fenton-like　metal-based　CDT　agents.　Intracellular　glutathione　(GSH)　with　.OH　scavenging　ability　greatly　reduces　CDT　efficacy.　A　self-reinforcing　CDT　nanoagent　based　on　MnO2　is　reported　that　has　both　Fenton-like　Mn2+　delivery　and　GSH　depletion　properties.　In　the　presence　of　HCO3−,　which　is　abundant　in　the　physiological　medium,　Mn2+　exerts　Fenton-like　activity　to　generate　.OH　from　H2O2.　Upon　uptake　of　MnO2-coated　mesoporous　silica　nanoparticles　(MS@MnO2　NPs)　by　cancer　cells,　the　MnO2　shell　undergoes　a　redox　reaction　with　GSH　to　form　glutathione　disulfide　and　Mn2+,　resulting　in　GSH　depletion-enhanced　CDT.　This,　together　with　the　GSH-activated　MRI　contrast　effect　and　dissociation　of　MnO2,　allows　MS@MnO2　NPs　to　achieve　MRI-monitored　chemo–chemodynamic　combination　therapy.　©　2018　Wiley-VCH　Verlag　GmbH　&　Co.　KGaA,　Weinheim