Publication date: Jul 20, 2026
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.
| Concepts | Keywords |
|---|---|
| antiviral immunity | |
| artificial intelligence | |
| GSDMD | |
| hepatitis A virus | |
| kill-and-alert | |
| lytic cell death | |
| mRNA-LNP | |
| pyroptosis | |
| VIDA | |
| viral protease |
Semantics
| Type | Source | Name |
|---|---|---|
| pathway | REACTOME | Pyroptosis |
| drug | DRUGBANK | Spinosad |
| disease | MESH | hepatitis A |
| pathway | KEGG | Viral replication |