Here, we reported a designable pH-responsive system on the basis of coordination bonded metal-tannic acid (TA) networks on zein/quaternized chitosan (HTCC) nanoparticles (NPs). Zein/HTCC NPs has been developed as a promising delivery system for natural bioactives in our lab previously. The coordination bonds between either the "NH2-metal" or the "metal-TA" are sensitive to pH variations that would release encapsulated drugs under designated pH conditions. Metal-TA film-coated zein/HTCC NPs had a spherical structure with particle size of 110–120 nm. Doxorubicin (DOX) was used as a model anticancer drug for release study and cell viability. The in vitro release profile of DOX loaded metal-TA films coated zein/HTCC NPs (DOX-zein/HTCC-TA/metal NPs) showed a significant pH-responsiveness when changing the amount or the type of metal ions. In in vitro cell assays, the blank zein/HTCC-TA/metal NPs showed low cytotoxicity, but the DOX-loaded NPs exhibited a high cytotoxic activity against HepG2. To impart enhanced imaging properties of metal-TA films, we used EuIII to chelate with ligand named 2-thenoyltrifluoroacetone (TTA) to intense fluorescence intensities of EuIII-TA films so as to develop pH-responsive zein/HTCC-TA/metal NPs for anticancer drug delivery as well as cell imaging.