Therapeutic potential of combating cancer by restoring wild-type p53 through mRNA nanodelivery

Abstract

Among the tumor suppressor genes, TP53 is the most frequently mutated in human cancers, and most mutations are missense mutations causing production of mutant p53 (mutp53) proteins. TP53 mutations not only results in loss of function (LOH) as a transcription factor and a tumor suppressor, but also gain wild-type p53 (WTp53)-independent oncogenic functions that enhance cancer metastasis and progression (Yamamoto and Iwakuma, 2018; Zhang et al., 2022). TP53 has extensively been studied as a therapeutic target as well as for drug development and therapies, however with limited success. Achieving targeted therapies for restoration of WTp53 function and depletion or repair of mutant p53 (mutp53) will have far reaching implication in cancer treatment and therapies. This review briefly discusses the role of p53 mutation in cancer and the therapeutic potential of restoring WTp53 through the advances in mRNA nanomedicine.

Keywords: Gene therapy; Nanotechnology; Restoring wild-type p53; cancer; p53 mutant.

Fig. 1.

Created with BioRender.com Role of mutp53 in cancer: WTp53 activates a variety of genes responsible for cell differentiation, apoptosis, and DNA damage control. These gene products prevent accumulation of abnormal cells. Alternations in TP53 can result in 3 types of mutations each with different characteristics. The loss of function (LOF) and the dominant negative mutation (DN) prevents activation of canonical WTp53 target genes whereas the gain of function (GOF) mutations result in activation of non-canonical p53 target genes resulting in cellular imbalance.

Fig. 2.

Created with BioRender.com Strategies to target p53 mutations: Mutp53 can lead to imbalance in the cells resulting in malignant transformation of the cell. The strategies to restore the activity of mutp53 include restoring conformation or function of mutp53, degradation of mutp53, and synthetic lethality. There are also efforts of exogeneous restoration of the TP53 gene or RNA to restore the function of WTp53. This includes use of viral vectors, the CRISPAR-cas9 technology, and/or mRNA therapy.

Fig. 3.

Created with BioRender.com mRNA structure and optimization. mRNA is a negatively charged molecule with distinctive regions. Each distinctive region serves specific purpose which can be optimized for mRNA to be used therapeutically.