Restoration of p53 function via hybrid strontium sulfite nanoparticles modified LNP improves the antitumor efficacy in breast cancers.

The astounding success of mRNA empowers the diverse application of mRNA therapeutics in multiple genetic disorders. Besides the vaccines, the rational design of mRNA drugs has been explored widely to target the undruggable gene therapy for managing cancer. Restoration of the p53 tumor suppressor gene via introducing foreign p53-mRNA therapeutics may inhibit the growth and development of tumors. Since the development of mRNA transporting vehicles, liposome-based nanoparticles are the mainstay and are widely used in several ex vivo and clinical studies. But the delivery of mRNA outside the immune cells and hepatocytes for protein replacement therapy through systemic administartion is very limited and requires additional optimization. Here, we modified classical LNP (lipid nanoparticles) with SSNs (strontium sulfite nanoparticles) and complexed the LNP with p53 mRNA to improve the delivery efficiency of p53 mRNA. We assumed that restoration of p53 function in breast tumor cells might improve antitumor efficacy against breast cancer. We screened the SSNs-LNP to get the favorable physicochemical properties and to improve the delivery efficiency. The SSNs-LNP showed a threefold increase of luciferase gene expression in breast cancer cell lines compared to the classical LNP. In the animal model, the SSNs-LNP improved the biological stability and tumor targeting efficiency and restored the expression of p53, resulting in a significant reduction of tumor volume. Thus, we anticipate that the hybrid SSNs-LNP particles could be a translatable nanocarrier system in transporting mRNA drugs for the treatment of cancers.