Cancer hallmarks allow the complexity and heterogeneity of tumor biology to be better understood, leading to the discovery of various promising targets for cancer therapy. An amorphous iron oxide nanoparticle (NP)-based RNAi strategy is developed to co-target two cancer hallmarks. The NP technology can modulate the glycolysis pathway by silencing MCT4 to induce tumor cell acidosis, and concurrently exacerbate oxidative stress in tumor cells via the Fenton-like reaction. This strategy has the following features for systemic siRNA delivery: 1)siRNA encapsulation within NPs for improving systemic stability; 2)effective endosomal escape through osmotic pressure and/or endosomal membrane oxidation; 3)small size for enhancing tumor tissue penetration; and 4)triple functions (RNAi, Fenton-like reaction, and MRI) for combinatorial therapy and invivo tracking.