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<p>Sepsis, a life-threatening condition arising from a dysregulated host response to infection, remains a significant clinical challenge with limited therapeutic options. RNA editing presents a promising avenue for modulating gene expression to attenuate the inflammatory cascade characteristic of sepsis. Here, we introduce an approach utilizing chemogenetic activation of CasRx-based RNA editing via bioengineered lentiviruses for the treatment of sepsis. Our strategy involves the targeted delivery of biomineralized lentiviral vectors encoding RNA-editing enzymes and chemogenetic switches to M1 macrophage populations implicated in sepsis pathogenesis. Upon the administration of a small molecule ligand, the chemogenetic switches activate the RNA-editing tool, CasRx, thereby enabling precise and repeated downregulation of <i>NLRP3</i> mRNA. We demonstrate the efficacy and repeatability of this viral-based approach in mouse models of sepsis, highlighting its potential as a versatile therapeutic strategy for mitigating sepsis-induced inflammation. This study underscores the utility of chemogenetic technologies in harnessing the power of RNA editing for the treatment of sepsis and other inflammatory disorders.</p>

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In vivo chemogenetic RNA editing of macrophages by bioengineered viruses for sepsis treatment

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月31日

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  • Wensong Xi,
  • Youcui Xu,
  • Weiwei Bao,
  • Zhixing Ding,
  • Hu Xiao,
  • Jiamin Yang,
  • Xiaojie Yan,
  • Yuan Ping

摘要

Sepsis, a life-threatening condition arising from a dysregulated host response to infection, remains a significant clinical challenge with limited therapeutic options. RNA editing presents a promising avenue for modulating gene expression to attenuate the inflammatory cascade characteristic of sepsis. Here, we introduce an approach utilizing chemogenetic activation of CasRx-based RNA editing via bioengineered lentiviruses for the treatment of sepsis. Our strategy involves the targeted delivery of biomineralized lentiviral vectors encoding RNA-editing enzymes and chemogenetic switches to M1 macrophage populations implicated in sepsis pathogenesis. Upon the administration of a small molecule ligand, the chemogenetic switches activate the RNA-editing tool, CasRx, thereby enabling precise and repeated downregulation of NLRP3 mRNA. We demonstrate the efficacy and repeatability of this viral-based approach in mouse models of sepsis, highlighting its potential as a versatile therapeutic strategy for mitigating sepsis-induced inflammation. This study underscores the utility of chemogenetic technologies in harnessing the power of RNA editing for the treatment of sepsis and other inflammatory disorders.