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<p>Innate immune activation is a major driver of unmodified in vitro–transcribed (IVT) mRNA degradation; however, how modified IVT mRNAs are degraded, and the related regulation mechanisms, remain poorly understood. Through a focused screen of viral- and host-derived immune suppressors, we identify 13 factors that enhance mRNA performance, with SOCS1 and the coronaviral membrane protein (M) emerging as the most potent. Multi-omics analyses reveal that pseudouridine-modified IVT mRNA undergoes rapid deadenylation and predominant 3′−5′ decay, followed by bidirectional degradation, closely resembling endogenous mRNA decay kinetics, and is extensively associated with canonical mRNA decay machineries. Mechanistically, IVT mRNA activates IFN-β signaling, which promotes processing body (P-body) formation and XRN1-mediated 5′−3′ degradation. Suppression of IFN signaling by SOCS1 or M markedly enhances mRNA expression across diverse cell types, organoid systems, and murine disease models. Together, these findings define a type I interferon–P-body–XRN1 axis that constrains modified IVT mRNA stability and provides a framework for enhancing mRNA therapeutics.</p>

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Hijacking innate immunity to enhance mRNA therapeutics by blocking IFN-P-body-XRN1 axis-mediated degradation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月17日

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  • Tinghong Zhang,
  • Xing Peng,
  • Jinling Qin,
  • Binqiang Zhu,
  • Shuaihua Zhang,
  • Shijie Deng,
  • Zhimin Song,
  • Yulong Han,
  • Hui Zheng,
  • Jingjing Chen,
  • Yun Zhang,
  • Yaofeng Wang,
  • Jingyuan Zhang,
  • Yumin Zhou,
  • Pixin Ran,
  • Ningyi Shao,
  • Bin Zhu,
  • Yunshen Chan,
  • Shu Meng

摘要

Innate immune activation is a major driver of unmodified in vitro–transcribed (IVT) mRNA degradation; however, how modified IVT mRNAs are degraded, and the related regulation mechanisms, remain poorly understood. Through a focused screen of viral- and host-derived immune suppressors, we identify 13 factors that enhance mRNA performance, with SOCS1 and the coronaviral membrane protein (M) emerging as the most potent. Multi-omics analyses reveal that pseudouridine-modified IVT mRNA undergoes rapid deadenylation and predominant 3′−5′ decay, followed by bidirectional degradation, closely resembling endogenous mRNA decay kinetics, and is extensively associated with canonical mRNA decay machineries. Mechanistically, IVT mRNA activates IFN-β signaling, which promotes processing body (P-body) formation and XRN1-mediated 5′−3′ degradation. Suppression of IFN signaling by SOCS1 or M markedly enhances mRNA expression across diverse cell types, organoid systems, and murine disease models. Together, these findings define a type I interferon–P-body–XRN1 axis that constrains modified IVT mRNA stability and provides a framework for enhancing mRNA therapeutics.