A significant percentage of human cancers harbor missense mutations in the TP53 gene and express highly stabilized mutant p53 protein (mutp53) with tumor‐promoting gain‐of‐function (GOF) properties. Inducing mutp53 degradation is a viable precision anti‐tumor therapeutic strategy. Based on the previously reported finding that a zinc‐curcumin compound induced mutp53 degradation, a series of ZnFe nanoparticles (ZnFe NPs) are synthesized and it is found that ZnFe‐4, with an Zn:Fe ratio of 1:2, exhibits outstanding mutp53‐degrading capability. ZnFe‐4 induced ubiquitination‐mediated proteasomal degradation of several different mutp53 species, but not the wild‐type p53 protein. Cellular internalization, intracellular Zn++ elevation and increased ROS are all necessary for ZnFe‐4‐induced mutp53 degradation. Degradation of mutp53 by ZnFe‐4, abrogated mutp53‐manifested GOF, leading to increased p21 expression, cell cycle arrest, reduced cell proliferation and cell migration, and cell demise. ZnFe‐4 also sensitized to cisplatin‐elicited killing in p53 S241F ES‐2 ovarian cancer cells, and dramatically improved the therapeutic efficacy of cisplatin in a subcutaneous ES‐2 tumor model. The potential clinical utility of ZnFe‐4 is further demonstrated in an orthotopically‐implanted p53 Y220C patient‐derived xenograft (PDX) breast cancer model. ZnFe‐4 is the first reported mutp53‐degrading nanomaterial, and further materials engineering may lead to the development of zinc‐based nanoparticles with minimal toxicity and maximized mutp53‐degrading capability.
More than half of human malignant tumors harbor TP53 gene mutations, most of which are point mutations within the DNA-binding domain of TP53, resulting in mutant p53 (mutp53) protein stabilization and accumulation in the cell and enhanced tumor progression. Depletion of mutp53 through the autophagy or proteasome pathway is considered the most direct strategy to target mutp53 for tumor treatment. However, due to the lack of specific autophagy receptors and the insufficient level of autophagy in tumor cells, targeted degradation of mutp53 by nanomaterials via the autophagy pathway has not been reported. Here, we propose a type of "nanoreceptors" (denoted NRs) that mimics selective autophagy receptors and develop a new platform for targeted degradation of mutp53. The NRs specifically bind mutp53 in tumor cells via mutp53-binding peptide (MBP). In addition, the level of cell autophagy is greatly increased due to the incorporated of cationic lipid. As a result, the NRs effectively degrade mutp53 through the autophagy pathway with complete autophagic flux. The knockout of ATG5, an essential autophagy-related gene, significantly inhibited the NRs-induced degradation of mutp53, demonstrating the critical role of autophagy in this effect. Subsequently, the degradation of mutp53 by the NRs abrogated mutp53-conferred gain-of-function (GOF) phenotypes, including enhanced cell proliferation and cell migration and reduced sensitivity to cisplatin (CDDP). Last, Pt(IV)-loaded NRs (NRs/Pt, consisting of Pt(IV) prodrug encapsulated in the NRs) showed outstanding synergistic antitumor effects in an ES-2 ovarian cancer model and a patient-derived xenograft (PDX) ovarian cancer model. Collectively, our study suggests the use of NRs/Pt as a new biomimetic nanoplatform for regulating autophagy, providing new ideas for precise tumor treatments that target mutp53.
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