Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition

Abstract

Redox-sensitive mRNA nanoparticles help kill tumors by restoring p53 expression. p53 makes a comeback One reason that cancer cells are so difficult to kill is that they often lack p53, a key tumor suppressor that promotes apoptosis. To address this problem, Kong et al. devised a way to restore p53 expression in tumors by delivering p53-mRNA in nanoparticles. To minimize damage to healthy tissues, the authors used redox-responsive particles, taking advantage of tumors’ relative hypoxia. The use of mRNA rather than DNA provided an additional safeguard because mRNA acts directly in the cytoplasm, without integrating into host cells’ DNA and introducing mutations. The authors tested their approach in multiple models in vitro and in vivo, with promising results. 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.