The dose-related adverse effects of MDM2-P53 inhibitors have caused significant concern in the development of clinical safe anticancer agents.Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2-P53 interaction.The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53.The new homo-PROTACs are designed to induce self-degradation of MDM2.The results of the investigation have shown that PROTAC 11a efficiently dimerizes MDM2 with highly competitive binding activity and induces proteasome-dependent self-degradation of MDM2 in A549 non-small cell lung can-cer cells.Furthermore,markedly,enantiomer 11a-1 exhibits potent in vivo antitumor activity in A549 xenograft nude mouse model,which is the first example of homo-PROTAC with in vivo therapeutic po-tency.This study demonstrates the potential of the homo-PROTAC as an alternative chemical tool for tumorigenic MDM2 knockdown,which could be developed into a safe therapy for cancer treatment.