在许多癌症中，TP53基因的点突变发生在DNA结合域内，导致细胞中大量突变型p53蛋白（mutp53）的出现，这些蛋白具有促进肿瘤形成的特性。针对p53突变的癌症的一个潜在和简单的策略 involves 诱导自噬或蛋白酶降解。根据先前报道的研究结果，提高mutp53细胞的氧化状态是针对mutp53的可行方法。然而，之前报道的纳米颗粒缺乏足够的特异性去调节肿瘤细胞中的ROS，从而导致健康细胞不良毒性。我们在这里展示，二氧化铈（CeO2）纳米颗粒在肿瘤细胞中产生更高水平的ROS，相比于健康细胞，证明CeO2纳米颗粒在癌细胞中的独特特性提供了一个针对mutp53降解的可行解决方案。CeO2纳米颗粒通过K48泛素化依赖性降解广谱mutp53蛋白，这种方式取决于mutp53与热休克蛋白Hsp90/70的解离和ROS的增加。如预期，CeO2纳米颗粒降解mutp53消除了mutp53表现的功能增益（GOF），导致细胞增殖和迁移减少，并显著提高了BxPC-3 mutp53肿瘤模型的治疗效果。总之，CeO2纳米颗粒在mutp53癌细胞中特异性地增加ROS，在mutp53癌症治疗上显示出特异性疗效，并在我们的研究中提供了应对mutp53降解所带来挑战的有效解决方案。 © 2023. The Author(s).

In a significant proportion of cancers, point mutations of TP53 gene occur within the DNA-binding domain, resulting in an abundance of mutant p53 proteins (mutp53) within cells, which possess tumor-promoting properties. A potential and straightforward strategy for addressing p53-mutated cancer involves the induction of autophagy or proteasomal degradation. Based on the previously reported findings, elevating oxidative state in the mutp53 cells represented a feasible approach for targeting mutp53. However, the nanoparticles previous reported lacked sufficient specificity of regulating ROS in tumor cells, consequently resulted in unfavorable toxicity in healthy cells.We here in showed that cerium oxide CeO2 nanoparticles (CeO2 NPs) exhibited an remarkable elevated level of ROS production in tumor cells, as compared to healthy cells, demonstrating that the unique property of CeO2 NPs in cancer cells provided a feasible solution to mutp53 degradation. CeO2 NPs elicited K48 ubiquitination-dependent degradation of wide-spectrum mutp53 proteins in a manner that was dependent on both the dissociation of mutp53 from the heat shock proteins Hsp90/70 and the increasing production of ROS. As expected, degradation of mutp53 by CeO2 NPs abrogated mutp53-manifested gain-of-function (GOF), leading to a reduction in cell proliferation and migration, and dramatically improved the therapeutic efficacy in a BxPC-3 mutp53 tumor model.Overall, CeO2 NPs increasing ROS specifically in the mutp53 cancer cells displayed a specific therapeutic efficacy in mutp53 cancer and offered an effective solution to address the challenges posed by mutp53 degradation, as demonstrated in our present study.© 2023. The Author(s).