How Viral Proteases Trigger Lytic Cell Death for Universal mRNA Therapy

Highlights

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    Engineered GSDMs are tailored as VIDAs to sense viral protease
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    VIDA is inert without infection and has potent antiviral effects in vitro and in vivo
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    VIDA elicits a “kill-and-alert” antiviral immune response in mice
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    AI-driven accelerated evolution generates safer and more potent VIDAs


Summary

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.

Read full article at:
https://www.sciencedirect.com/science/article/abs/pii/S0092867426007518


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