Photosensitizer　in　photodynamic　therapy　(PDT)　accumulates　in　both　tumor　and　adjacent　normal　tissue　due　to　low　selective　biodistribution,　results　in　undesirable　side　effect　with　limited　clinic　application.　Herein,　an　intelligent　nanoplatform　is　reported　that　selectively　acts　as　reactive　oxygen　species　(ROS)　scavenger　in　normal　tissue　but　as　ROS　generator　in　tumor　microenvironment　(TME)　to　differentially　control　ROS　level　in　tumor　and　surrounding　normal　tissue　during　PDT.　By　down-regulating　the　produced　ROS　with　dampened　cytokine　wave　in　normal　tissue　after　PDT,　the　nanoplatform　reduces　the　inflammatory　response　of　normal　tissue　in　PDT,　minimizing　the　side　effect　and　tumor　metastasis　in　PDT.　Alternatively,　the　nanoplatform　switches　from　ROS　scavenger　to　generator　through　the　glutathione　(GSH)　responsive　degradation　in　TME,　which　effectively　improves　the　PDT　efficacy　with　reduced　GSH　level　and　amplified　oxidative　stress　in　tumor.　Simultaneously,　the　released　Mn　ions　provide　real-time　and　in　situ　signal　change　of　magnetic　resonance　imaging　(MRI)　to　monitor　the　reversal　process　of　catalysis　activity　and　achieve　accurate　tumor　diagnosis.　This　TME-responsive　ROS　scavenger/generator　with　activable　MRI　contrast　may　provide　a　new　dimension　for　design　of　next-generation　PDT　agents　with　precise　diagnosis,　high　therapeutic　efficacy,　and　low　side　effect.　©　2022　Wiley-VCH　GmbH.