Loss of function in tumor suppressor genes is commonly associated with the onset/progression of cancer and treatment resistance. The p53 tumor suppressor gene, a master regulator of diverse cellular pathways, is frequently altered in various cancers, for example, in ~36% of hepatocellular carcinomas (HCCs) and ~68% of non-small cell lung cancers (NSCLCs). Current methods for restoration of p53 expression, including small molecules and DNA therapies, have yielded progressive success, but each has formidable drawbacks. Here, a redox-responsive nanoparticle (NP) platform is engineered for effective delivery of p53-encoding synthetic messenger RNA (mRNA). We demonstrate that the synthetic p53-mRNA NPs markedly delay the growth of p53-null HCC and NSCLC cells by inducing cell cycle arrest and apoptosis. We also reveal that p53 restoration markedly improves the sensitivity of these tumor cells to everolimus, a mammalian target of rapamycin (mTOR) inhibitor that failed to show clinical benefits in advanced HCC and NSCLC. Moreover, cotargeting of tumor-suppressing p53 and tumorigenic mTOR signaling pathways results in marked antitumor effects in vitro and in multiple animal models of HCC and NSCLC. Our findings indicate that restoration of tumor suppressors by the synthetic mRNA NP delivery strategy could be combined together with other therapies for potent combinatorial cancer treatment.

中文翻译：

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合成的mRNA纳米粒子介导的p53肿瘤抑制因子的修复可使p53缺陷型癌症对mTOR抑制敏感。

肿瘤抑制基因的功能丧失通常与癌症的发作/进展和治疗抵抗有关。p53抑癌基因是多种细胞途径的主要调控因子，在多种癌症中经常发生变化，例如，约36％的肝细胞癌（HCC）和约68％的非小细胞肺癌（NSCLC）。当前恢复p53表达的方法，包括小分子和DNA疗法，已经取得了逐步的成功，但是每种方法都有巨大的缺点。在这里，设计了氧化还原反应性纳米颗粒（NP）平台，用于有效递送编码p53的合成信使RNA（mRNA）。我们证明了合成的p53-mRNA NPs通过诱导细胞周期停滞和凋亡显着延迟了p53无HCC和NSCLC细胞的生长。我们还发现p53修复显着提高了这些肿瘤细胞对依维莫司的敏感性，依维莫司是雷帕霉素（mTOR）抑制剂的哺乳动物靶标，在晚期HCC和NSCLC中未显示出临床益处。而且，在体外以及在HCC和NSCLC的多种动物模型中，肿瘤抑制性p53和致瘤mTOR信号通路的共同靶向导致明显的抗肿瘤作用。我们的研究结果表明，通过合成的mRNA NP递送策略恢复肿瘤抑制因子可与其他有效的组合性癌症治疗疗法结合起来。肿瘤抑制性p53和致瘤性mTOR信号通路的共同靶向可在体外以及在HCC和NSCLC的多种动物模型中产生显着的抗肿瘤作用。我们的发现表明，通过合成的mRNA NP递送策略恢复肿瘤抑制因子可与其他有效的组合癌治疗疗法结合起来。肿瘤抑制性p53和致瘤性mTOR信号通路的共同靶向可在体外以及在HCC和NSCLC的多种动物模型中产生显着的抗肿瘤作用。我们的发现表明，通过合成的mRNA NP递送策略恢复肿瘤抑制因子可与其他有效的组合癌治疗疗法结合起来。