Nanoreceptors promote mutant p53 protein degradation by mimicking selective autophagy receptors

Abstract

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.