A synthetic system for RNA-responsive pyroptosis based on type III-E CRISPR nuclease-protease

TL;DR

The paper introduces DAMAGE, a CRISPR-based system that triggers pyroptosis in response to specific RNA, enabling targeted elimination of harmful cells.

Contribution

DAMAGE integrates gasdermins with type III-E CRISPR to enable RNA-responsive pyroptosis for targeted cell death.

Findings

DAMAGE can selectively eliminate virus-infected, cancerous, and senescent cells.

The system shows potential for use in mRNA-LNP therapies.

It offers a controllable method for inducing pyroptosis in RNA-heterogeneous diseases.

Abstract

Pyroptosis plays a crucial role in immune defense against infections and endogenous threats by eliminating harmful cells and modulating the immune response through inflammation. However, the natural activation of pyroptosis involves intricate signaling pathways, posing significant challenges for its artificial manipulation in research and therapies. Here, we present DAMAGE (Death Manipulation Gene), an innovative system that integrates gasdermins within the type III-E CRISPR framework, enabling the specific recognition of target RNA (tgRNA) and triggering pyroptosis. This mechanism allows DAMAGE to selectively identify and eliminate virus-infected, cancerous, and senescent cells, all of which exhibit altered RNA transcriptomes. Additionally, DAMAGE exhibits considerable promise as a platform for mRNA-LNP therapy. Our study highlights the potential of this CRISPR-based system in the controllable induction of pyroptosis, offering an innovative therapeutic strategy for treating RNA-heterogeneous diseases.

Pyroptosis is a programmed cell death controlled by complex pathways, making it hard to induce selectively for targeted cell elimination. Here, the authors developed DAMAGE, a system that combines pyroptosis with type III-E CRISPR to detect specific RNA and trigger cell death

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