Simultaneously supplementing Wtp53 and degrading Mutp53 using a virus-mimicking mRNA delivery system to restore P53's autonomous anti-cancer function

Restoring P53's autonomous anti-cancer function through P53 mRNA delivery is a promising anti-tumor strategy. Yet, in tumors harboring mutant P53, the existing mutant P53 (Mutp53) would interferes with the anti-tumor function of Wtp53 through dominant-negative effect. Herein, we designed Vir-Z@R, a P53-repair nanosystem based on a virus-mimicking nanostructure to deliver P53 mRNA and Zn(II) into tumor cells. By supplementing Wtp53 through P53 mRNA delivery and promoting the degradation of mutant P53 via a zinc ion-mediated proteasomal pathway, Vir-Z@R restores the autonomous tumor-suppressive function of P53 and induce tumor cell death through multiple mechanisms (interfering with energy metabolism and inducing apoptosis), leading to delayed tumor growth and prolonged survival in mice with Mutp53. This study provides a strategy for treatment of P53-mutant tumor.