mRNA stability and translation efficiency are pivotal for therapeutic success, as rapid degradation limits protein yield. Stability is bolstered by structural modifications: the 5′ cap (e.g., anti-reverse cap analog, ARCA) prevents 5′ exonucleolytic decay and aids ribosome scanning; optimized UTRs (e.g., β-globin 5′ UTR) minimize secondary structures and miRNA binding sites to prolong half-life; and poly(A) tails (100–250 nt) recruit poly(A)-binding proteins for circularization and protection. Nucleoside analogs like pseudouridine (Ψ) or N1-methylpseudouridine reduce TLR7/8 recognition, curbing innate immune activation while enhancing translation via improved codon usage.
Codon optimization increases G-C content and uses synonymous codons for efficient ribosomal decoding, correlating with higher protein output. Translation elongation couples with stability; slow codons stabilize mRNAs by limiting decapping. In vaccines like BNT162b2, these tweaks yield 10-fold expression boosts. Challenges include cell-type variability, addressed by sequence mining from stable transcripts.
Beyond vaccines, stable mRNAs enable protein replacement therapies. Future directions involve AI-driven sequence design for universal platforms.
References: PMC (2021) for modifications, PMC (2019) for codon effects. Word count: 242.
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