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

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.

A Novel Top-Down Synthesis of Ultrathin 2D Boron Nanosheets for Multimodal Imaging-Guided Cancer Therapy.

Single atom nonmetal 2D nanomaterials have shown considerable potential in cancer nanomedicines, owing to their intriguing properties and biocompatibility. Herein, ultrathin boron nanosheets (B NSs) are prepared through a novel top-down approach by coupling thermal oxidation etching and liquid exfoliation technologies, with controlled nanoscale thickness. Based on the PEGylated B NSs, a new photonic drug delivery platform is developed, which exhibits multiple promising features for cancer therapy and imaging, including: i) efficient NIR-light-to-heat conversion with a high photothermal conversion efficiency of 42.5%, ii) high drug-loading capacity and triggered drug release by NIR light and moderate acidic pH, iii) strong accumulation at tumor sites, iv) multimodal imaging properties (photoacoustic, photothermal, and fluorescence imaging), and v) complete tumor ablation and excellent biocompatibility. As far as it is known, this is the first report on the top-down fabrication of ultrathin 2D B NSs by the combined thermal oxidation etching and liquid exfoliation, as well as their application as a multimodal imaging-guided drug delivery platform. The newly prepared B NSs are also expected to provide a robust and useful 2D nanoplatform for various biomedical applications.