As　a　typical　chemodynamic　therapy　(CDT),　the　Fenton　reaction　holds　great　promise　in　cancer　therapy　for　its　effective　generation　of　the　cytotoxic　hydroxyl　radical　(.OH)　in　situ　which　induces　cancer　cell　apoptosis.　However,　the　tumor　microenvironment　is　insufficient　to　meet　the　optimal　conditions　for　Fenton　reaction,　which　greatly　reduces　the　rate　of　Fenton　reaction　and　the　therapeutic　effect　of　CDT,　thereby　hindering　its　application　in　cancer　therapy.　Herein,　a　novel　biocompatible　nanogel　comprised　of　ferroferric　oxide　modified　β-cyclodextrin　(Fe3O4@β-CD),　glucose　oxidase　(GOX),　and　ferrocene　(Fc)　was　fabricated　using　the　host-guest　self-assembly　method　for　synergistic　tumor　therapy　(Fe3O4−GOX　nanogel,　FGgel).　In　the　tumor　microenvironment,　the　intratumoral　hydrogen　peroxide　(H2O2)　could　oxidize　Fc,　leading　to　the　disintegration　of　the　FGgel　and　the　release　of　GOX.　Subsequently,　the　released　GOX　could　catalyze　glucose　to　produce　gluconic　acid　and　promote　the　production　of　H2O2.　Meanwhile,　in　acidic　conditions,　F3O4　served　as　the　Fenton　reagent　to　convert　excessive　H2O2　into　highly　toxic　.OH　which　finally　induces　tumor　cell　apoptosis.　Extensive　in　vitro　and　in　vivo　studies　have　confirmed　that　FGgel　can　effectively　inhibit　tumor　cell　growth　with　high　tumor　specificity　and　good　biocompatibility.　The　excellent　anticancer　efficiency　of　FGgel　indicates　that　it　is　an　ideal　H2O2-activated　nanosystem.　As　an　excellent　platform　to　harness　the　highly　toxic　reactive　oxygen　species　in　nanomedicine　for　specific　cancer　therapy,　this　strategy　may　open　new　doors　for　further　development　of　progressive　therapeutic　systems.　©　2020　Wiley-VCH　Verlag　GmbH　&　Co.　KGaA,　Weinheim