In Water Margin, the 108 heroes are ranked according to 36 Heavenly Spirits and 72 Earthly Fiends. This ranking—ostensibly divine—was actually designed by Song Jiang to stabilize morale and maintain control. Similarly, mRNA drug development requires sequence optimization to enhance exogenous protein expression efficiency and induce more neutralizing antibodies.

mRNA has five structural regions: 5' cap, 5' untranslated region (UTR) , open reading frame (ORF) , 3' UTR, and poly(A) tail. Sequence optimization includes codon optimization, 5' UTR selection, and 3' UTR selection—with codon optimization being the simplest.

The 20 common amino acids are encoded by 64 codons (with 3 stop codons). This means multiple codons encode the same amino acid—these are called synonymous codons. Different organisms and cell types have different codon usage frequencies—each has its own "preference." High-frequency ("optimal") codons correspond to high-abundance tRNAs. Replacing low-frequency rare codons with high-frequency common codons significantly improves mRNA stability and protein expression efficiency.

Beyond codon optimization, mRNA secondary structure has become another key direction. More stable secondary structures correlate with longer half-life and higher protein yield. However, finding an mRNA sequence with sufficiently stable secondary structure, high translation efficiency, and optimal codon usage is far more complex than ranking 108 heroes. With AI and high-throughput validation, new pathways for mRNA sequence optimization are emerging.