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Lapatinib is a dual EGFR and HER2 inhibitor that is used to treat HER2-overexpressing cancers. However, its poor water solubility hinders its clinical use. Proteobionics is a promising way to solve this problem.Lapatinib-incorporated core–shell nanoparticles (LTNPs) were prepared and characterized by cryo-transmission electron micrograph. Then, in vitro cellular uptake and in vivo glioma targeting effect were determined by both qualitative and quantitative studies. After that, anti-glioma effect of LTNPs was determined by cytotoxicity and life-span study. Finally, the mechanism was elucidated by western blot.LTNPs elevated the water solubility of the drug from 0.007 mg/mL to over 10 mg/mL, which was better than most commercially available injection solvents. Glioma is an increasing threat to humans’ health. Here, we evaluated the treatment effects of LTNPs on glioma and explored their mechanism. LTNPs were taken up by U87 cells, inhibiting their proliferation and causing a G2 phase arrest. The uptake was energy-, time- and concentration-dependent, and several pathways were involved. LTNPs inhibited the phosphorylation of the survival (phosphatidylinositol 3-kinase/Akt) pathways, which caused the anti-proliferative effect. In vivo experiments determined that LTNPs were distributed to and accumulated in glioma by the enhanced permeation and retention effect. The distribution was colocalized with SPARC expression, which may mediate endocytosis. In pharmacokinetics and glioma distribution study, LTNPs displayed a higher blood AUC, glioma concentration and glioma/brain ratio than Tykerb. A pharmacodynamics study confirmed that LTNPs could significantly expand the median survival time of glioma-bearing mice at a cumulative dose of 40 mg/kg, which was only 5% of the dose of the commercially available lapatinib tablet (Tykerb).LTNPs effectively increased the solubility of lapatinib and improved the treatment of glioma.