A poly(amidoamine) dendrimer (PAMAM, G5) based drug delivery system was developed for the treatment of glioma. PAMAM was modified with polyethylene glycol (PEG) to improve its in vivo stability and reduce immunogenicity. Further, the internalized RGD (iRGD) recognition ligand of the integrin alpha v beta 3 receptor and the blood-brain barrier (BBB)-targeting group TGN were introduced. Arsenic trioxide (ATO) was loaded into the internal cavity through electrostatic interactions to form iRGD/TGN-PEG-PAMAM-ATO. The drug delivery system of iRGD/TGN dual-modified PAMAM, which entrapped ATO, had a high entrapment efficiency of approximately 71.92% +/- 1.17% and displayed sustainable acid-dependent drug release. Assessment of antiglioma effects revealed that survival rate was significantly higher in the iRGD/TGN comodified group than in the other groups. Overall, iRGD/TGN-based dual targeting by combining nanocarriers and targeting technology increased the amount of drug that crossed BBB, thus achieving targeted enrichment and activation of the drug in tumor tissue. This activation ultimately increased therapeutic effects and reduced side effects of ATO. This strategy using a multistep-targeted delivery system shows great promise for targeted glioma therapy. (c) 2020 Published by Elsevier Inc.