密码子依赖的N1-乙基假尿苷修饰mRNA翻译降低先天免疫同时保留疫苗免疫原性
Codon-dependent translation of N1-ethylpseudouridine-modified mRNA reduces innate immunity while preserving vaccine immunogenicity
mRNA疫苗是快速开发疫苗的通用平台，但核苷修饰需要兼顾翻译效率和先天免疫激活。本研究评估了N1-乙基假尿苷（Et1Ψ）能否替代常用的N1-甲基假尿苷（m1Ψ）。结果显示，Et1Ψ修饰的mRNA对密码子有独特敏感性：UUU密码子增多会降低蛋白表达，而通过同义密码子优化去除UUU后，其在多种细胞中的翻译效率可恢复到与m1Ψ相当的水平。Et1Ψ在体外和体内都能持续降低先天免疫激活；用于SARS-CoV-2刺突蛋白和四价登革热包膜结构域III等疫苗抗原时，能诱导与m1Ψ相当的体液和细胞免疫应答及中和活性。研究提示密码子与修饰的相互作用是mRNA疗法设计的关键原则。
为什么推荐给您：新型核苷修饰Et1Ψ配伍密码子优化，提供兼顾低免疫激活与高效表达的mRNA平台新设计原则。
不需要生物学背景，多打比方
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摘要Abstract
Messenger RNA (mRNA) vaccines are a versatile platform for rapid vaccine development; however, nucleoside modifications must be optimized to balance translational efficiency and innate immune activation. Here, we evaluated N1-ethylpseudouridine (Et1Ψ) as an alternative to the widely used N1-methylpseudouridine (m1Ψ). Et1Ψ-modified mRNA exhibited a distinct codon-dependent translational sensitivity, with increased UUU codon content leading to reduced protein expression. Importantly, synonymous codon optimization that eliminated UUU codons restored translation efficiency to levels comparable to those of m1Ψ-modified mRNA across multiple cell types. Despite this constraint, Et1Ψ consistently reduced innate immune activation in vitro and in vivo. Following codon optimization, Et1Ψ-modified mRNA supported robust protein expression comparable to that from m1Ψ-modified mRNA. When applied to vaccine antigens, including SARS-CoV-2 spike and tetravalent dengue envelope domain III constructs, Et1Ψ-modified mRNA elicited strong humoral and cellular immune responses, with neutralizing activity comparable to that of m1Ψ-modified mRNA. Collectively, these findings identify Et1Ψ as an alternative nucleoside modification that combines reduced innate immunogenicity with codon-aware sequence optimization, highlighting codon-modification interactions as a key design principle for mRNA therapeutics.