An intelligent　nanodrug　delivery　system　(Cu/ZIF-8@GOx-DOX@HA,　hereafter　CZGDH)　consisting　of　Cu-doped　zeolite　imidazolate　framework-8　(Cu/ZIF-8,　hereafter　CZ),　glucose　oxidase　(GOx),　doxorubicin　(DOX),　and　hyaluronic　acid　(HA)　was　established　for　targeted　drug　delivery　and　synergistic　therapy　of　tumors.　The　CZGDH　specifically　entered　tumor　cells　through　the　targeting　effect　of　HA　and　exhibited　acidity-triggered　biodegradation　for　subsequent　release　of　GOx,　DOX,　and　Cu2+　in　the tumor　microenvironment　(TME).　The　GOx　oxidized　the　glucose　(Glu)　in　tumor　cells　to　produce　H2O2　and　gluconic　acid　for　starvation　therapy　(ST).　The　DOX　entered　the　intratumoral　cell　nucleus　for　chemotherapy　(CT).　The　released　Cu2+　consumed　the　overexpressed　glutathione　(GSH)　in　tumor　cells　to　produce　Cu+.　The　generated　Cu+　and　H2O2　triggered　the　Fenton-like　reaction　to　generate　toxic　hydroxyl　radicals　(·OH),　which　disrupted　the　redox　balance　of　tumor　cells　and　effectively　killed　tumor　cells　for　chemodynamic　therapy　(CDT).　Therefore,　synergistic　multimodal　tumor　treatment　via　TME-activated　cascade　reaction　was　achieved.　The　nanodrug　delivery　system　has　a　high　drug　loading　rate　(48.3 wt%),　and　the　three-mode　synergistic　therapy　has　a　strong　killing　effect　on　tumor　cells　(67.45%).　Graphical　abstract:　(Figure　presented.)　©　The　Author(s),　under　exclusive　licence　to　Springer-Verlag　GmbH　Austria,　part　of　Springer　Nature　2024.