In　order　to　maximize　the　therapeutic　effect　and　and　minimize　the　systemtic　side　effect　of　the　small　molecule　anticancer　drugs,　biodegradable　drug　delivery　systems　(DDSs)　that　respond　to　tumor　microenvironment　(TME)　have　attracted　significant　attention.　Herein,　a　novel　redox/pH　dual-responsive　and　biodegradable　polyphosphazene　(PPZ)　nano-prodrugs　have　been　prepared　via　one-pot　crosslinking　of　vanillin　modified　DOX　(VMD,　acid-sensitive)　and　4,4′-dihydroxydiphenyl　disulfide　(HPS,　GSH-responsive)　with　hexachlorocyclotriphosphazene　(HCCP).　The　phenol　groups　of　the　as-synthesized　VMD　and　HPS　have　high　nucleophilic　substitution　activity　towards　HCCP　under　base　catalyst　and　afforded　PPZ　nano-prodrugs,　denoted　as　HCCP-VMD-HPS,　with　a　high　drug　loading　ratio　of　up　to　56.4　%.　As　expected,　the　skeleton　of　the　PPZ　consisting　of　imine　bonds　in　VMD　and　the　disulfide　bonds　in　HPS　and　cyclotriphosphazenes　inclined　to　be　decomposed　in　low　pH　conditions　and　high　level　of　GSH　environments.　The　antitumor　drug　DOX　was　found　to　be　controlled　released　in　TME　conditions　(extracellular,　pH∼6.8　and　endosomes,　lysosomes　pH∼5.0　with　∼10　mM　GSH),　rather　than　neutral　physiological　conditions　(pH　7.4　with　∼20　μM　GSH).　Moreover,　the　resulting　HCCP-VMD-HPS　nano-prodrug　have　obvious　cytotoxicity　to　cancer　cells　while　a　negligible　side　effect　to　normal　cells.　We　therefore　believe　that　the　prepared　redox/pH　dual-responsive　and　biodegradable　PPZ　DDSs　have　great　potential　in　various　field.　©　2021