CellJul 20, 2026

Viral enzyme-triggered cell self-destruction as a universal antiviral mRNA treatment

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 21, 2026

Abstract

Lipid nanoparticle-encapsulated VIDA mRNA abolished viral replication and shedding in vivo against hepatitis A virus.

Gasdermin (GSDM)-mediated pyroptosis may have untapped antiviral potential.
Viral protease-initiated lytic cell death (VID) is introduced as a new mRNA therapeutic platform.
VID activators (VIDAs) are engineered to selectively trigger cell death in virus-infected cells.
A coordinated 'kill-and-alert' mechanism may mitigate liver injury and prime immune responses.
The platform demonstrated effectiveness against multiple viruses, including Zika virus and SARS-CoV-2.
De novo cleavage motifs for SARS-CoV-2 were designed using artificial intelligence, resulting in optimized VIDAs.

Simplified

While gasdermin (GSDM)-mediated pyroptosis is a potent immune effector, its antiviral potential remains largely untapped. Here, we introduce viral protease-initiated lytic cell death (VID), a universal mRNA therapeutic platform inspired by the modular architecture of GSDM and the clinical success of mRNA vaccines. By engineering gasdermin-D (GSDMD) to harbor viral protease-specific cleavage motifs, we generated VID activators (VIDAs) that selectively trigger lytic cell death in virus-infected cells. Using hepatitis A virus (HAV) as a model, lipid nanoparticle (LNP)-encapsulated VIDA mRNA abolished viral replication and shedding in vivo and mitigated liver injury through a coordinated "kill-and-alert" mechanism that primes bystander immunity. The platform's versatility was further demonstrated against Zika virus (ZIKV) and SARS-CoV-2. Leveraging a generative artificial intelligence (AI) framework, we designed de novo cleavage motifs for the SARS-CoV-2 main protease, yielding optimized VIDAs with superior antiviral potency. Collectively, our study establishes VIDA mRNA as a versatile, broadly applicable strategy for combating diverse viral threats.