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.

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Phosphorus plays an indispensable role in energy metabolism, acid-base balance, and genetic substances transfer. As nanotechnology advances, plenty of phosphorus-based nanomaterials have been developed and widely used in the fields of biology and medicine. The size and structure of phosphorus-based nanomaterials give them unique physicochemical, optical, and biological properties, greatly increasing the variety of nanomedicine. The excellent properties further promote the applications of phosphorus-based nanomaterials in drug nanocarriers, tumor theranostics, biosensors, and bone formation. In this review, we first introduce the phosphorus science to unify current phosphorus-based nanomaterials and discuss their synthesis methods. Furthermore, the representative nanoplatforms utilizing the corresponding properties are highlighted. Finally, research development, potential challenges, and perspectives for further improvement of phosphorus-based nanomaterials in biomedicines are presented.