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Hong Chen,1–3,* Huizi Sha,2,* Lianru Zhang,2 Hanqing Qian,2 Fangjun Chen,2 Naiqin Ding,2 Liulian Ji,2 Anqing Zhu,2 Qiuping Xu,2 Fanyan Meng,2 Lixia Yu,2 Yan Zhou,3 Baorui Liu1,2 1The Comprehensive Cancer Centre, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China; 2The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, People’s Republic of China; 3Department of Oncology, Yixing People’s Hospital, Jiangsu, People’s Republic of China *These authors contributed equally to this work Background: There is currently much interest in cancer cell targeting and tumor penetrating for research and therapeutic purposes.Purpose: To improve targeting delivery of antitumor drugs to gastric cancer, in this study, a tumor-targeting biocompatible drug delivery system derived from erythrocyte membrane for delivering paclitaxel (PTX) was constructed.Methods: Erythrocyte membrane of human red blood cells (RBCs) were used for preparing of erythrocyte membrane-derived vesicles. 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(maleimide[polyethylene glycol]-3400) (DSPE-PEG-MAL), a phospholipid derivative, was used to insert tumor-targeting molecular into erythrocyte membrane-derived vesicles. A lipid insertion method was used to functionalize these vesicles without the need for direct chemical conjugation. Furthermore, a tumor-penetrating bispecific recombinant protein named anti-EGFR-iRGD was used for the first time in this work to enable nanosystem to target and penetrate efficiently into the tumor site.Results: Paclitaxel (PTX)-loaded anti-EGFR-iRGD-modified erythrocyte membrane nanosystem (anti-EGFR-iRGD-RBCm-PTX, abbreviated to PRP) were manufactured. PRP was spheroid, uniformly size, about 171.7±4.7 nm in average, could be stable in vitro for 8 days, and relea