Messenger ribonucleic acid (mRNA), an emerging class of novel nucleic acid therapeutics, is a type of single-stranded RNA using the DNA strand as a template for transcription, and it carries genetic information to guide protein synthesis. mRNA has enormous potential in the field of cancer therapy due to its versatility, rapid preparation, and low manufacturing cost. Despite some advances in the design of mRNA-based therapeutics, the lack of in vivo stability and ineffective delivery impede the broad clinical application of mRNA. Performing chemical modifications on mRNA and developing nanoparticle-based delivery system are significant approaches to overcome the inherent defects of mRNA. At present, the nanodelivery systems including lipid-based nanoparticles, polymer-based nanoparticles, and protein derivative–mRNA complexes are attracting growing interest. This chapter focuses on the structure and sequence optimization of mRNA, the application of mRNA cancer therapy, key biological delivery barriers, and recent advances in nanoparticle-based mRNA delivery strategies.