In this study, we report pH-responsive metal-based biopolymer nanoparticles (NPs) for tumor-specific chemotherapy. Here, aminated hyaluronic acid (aHA) coupled with 2,3-dimethylmaleic anhydride (DMA, as a pH-responsive moiety) (aHA-DMA) was electrostatically complexed with ferrous chloride tetrahydrate (FeCl2/4H2O, as a chelating metal) and doxorubicin (DOX, as an antitumor drug model), producing DOX-loaded Fe-based hyaluronate nanoparticles (DOX@aHA-DMA/Fe NPs). Importantly, the DOX@aHA-DMA/Fe NPs improved tumor cellular uptake due to HA-mediated endocytosis for tumor cells overexpressing CD44 receptors. As a result, the average fluorescent DOX intensity observed in MDA-MB-231 cells (with CD44 receptors) was ~7.9 × 102 (DOX@HA/Fe NPs, without DMA), ~8.1 × 102 (DOX@aHA-DMA0.36/Fe NPs), and ~9.3 × 102 (DOX@aHA-DMA0.60/Fe NPs). Furthermore, the DOX@aHA-DMA/Fe NPs were destabilized due to ionic repulsion between Fe2+ and DMA-detached aHA (i.e., positively charged free aHA) in the acidic environment of tumor cells. This event accelerated the release of DOX from the destabilized NPs. Our results suggest that these NPs can be promising tumor-targeting drug carriers responding to acidic endosomal pH.