Work

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

Year: 2025

Type: article

Abstract: 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. Sepsis remains a major clinical challenge due to dysregulated inflammation. Here, the authors develop a chemogenetic RNA-editing system using bioengineered lentiviruses to target and downregulate NLRP3 mRNA in inflammatory macrophages, offering a controllable and effective strategy for sepsis treatment.

Source: Nature Communications

DOI: 10.1038/s41467-025-67655-y