When mRNA meets gene editing

The critical challenge of gene therapy lies in delivering gene editing agents. Compared with DNA, while RNA is less stable and more accessible to degrade, it comes with the benefit of lower off-target effects since permanent insertion is not involved. This review focuses on mRNA-based delivery of gene editing agents, highlighting novel mRNA delivery systems. To provide context, a comparison is made between three main gene editing agents: programmable nucleases, base editors, and prime editors. The potential of Cas\pi and transposons is also discussed in this review. Additionally, a summary of four main barriers to mRNA-based in vivo delivery is provided. Furthermore, this review detailedly introduced different delivery systems, both viral (lentivirus) and non-viral vectors (genome editing via oviductal nucleic acids delivery, lipid nanoparticles, polymer-based nanoparticles, virus-like-particles, extracellular vesicles, and migrasome). Each delivery strategy is assessed by comparing its advantages and disadvantages to offer a comprehensive and objective overview of the delivery system. Moreover, we emphasized the vital role of the protein corona as a critical regulator for nanodelivery. Ultimately, we concluded the challenges of mRNA-based gene editing strategies (RNA stability, targeting, potential immunogenicity, cytotoxicity, heterogeneity, and rational design). The purpose of this review is to guide further research and provide a comprehensive analysis of mRNA-based in vivo delivery of gene editing agents in this promising field.