Lung cancer, as one of the most fatal cancers around the world, is responsible for the death of millions every year. Among various types of lung cancers, the ones overexpressing CD44 is usually associated higher cell proliferation with poorer prognosis. Therefore, finding a way to effectively treat CD44 positive lung cancer is urgently needed. Here in this study, negatively charged ultrasmall prussian blue nanoparticles (UPBNPs) was firstly synthesized and adsorbed to polyethyleneimine (PEI) together with glucose oxidase (Gox). Afterwards, the PEI was further complexed with hyaluronic acid (HA) to give a cascade reaction platform (HP/UPB-Gox) for CD44 positive lung cancer therapy. The HP/UPB-Gox with HA shell was able to positively target CD44 overexpressed A549 cells. Upon arriving at the tumor tissue, the Gox catalyzed the glucose of tumor to create H₂O₂, which further served as the substrate of UPBNPs, a peroxidase mimic, to finally give highly toxic hydroxyl radical (OH) for cancer therapy. Therefore, the cascade reaction formed between UPBNPs and Gox was expected to realize effective treatment on CD44 overexpressed lung cancer.