VIDA: A programmable gasdermin-mediated strategy to broaden mRNA therapeutics

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Pyroptosis, a gasdermin (GSDM)-driven form of inflammatory programmed cell death, has long been recognized for its dual function: direct elimination of infected or transformed cells and activation of the immune system via released cellular contents and pro-inflammatory mediators.¹ This positions pyroptosis as a highly attractive therapeutic modality²; however, translating this mechanism into safe, precisely targeted interventions has remained challenging, particularly for viral infections.

The success of mRNA-lipid nanoparticle (mRNA-LNP) vaccines has paved the way for repurposing this platform beyond prophylaxis.^3,4 Preclinical studies have demonstrated that LNP-delivered GSDM mRNA induces tumor regression in murine models,^5,6 yet its therapeutic application to viral infections remained unexplored. In our recent study published in Cell,⁷ we addressed this gap by engineering VIDA (viral protease-initiated lytic cell death activators), a programmable mRNA therapeutic platform that co-opts viral replication machinery to trigger host cell death (Figure 1).

Figure 1.

Mechanism-of-action schematic of mRNA vaccines and VIDA mRNA therapeutics

While vaccines and antiviral drugs have achieved remarkable success against individual pathogens, current strategies suffer from inherent limitations. Most are narrow-spectrum and prone to rapid resistance emergence, continually outpaced by viral mutation and diversification. Compounding this, many viruses establish latent reservoirs that evade immune detection during dormancy, while conventional antiviral agents typically inhibit viral replication without stimulating host immune responses—leaving patients vulnerable to reactivation and reinfection. VIDA addresses these unmet needs by exploiting a near-universal feature of viral biology.

Many viruses encode specific proteases at the early stage of infection to cleave their polyproteins into functional subunits. These enzymes recognize short, conserved substrate motifs with remarkable fidelity. Leveraging this evolutionary constraint, we rationally redesigned gasdermin-D (GSDMD) by replacing its native caspase cleavage site with viral protease-specific recognition sequences. This reprogramming ensures VIDA remains inert and becomes activated only upon cleavage by the cognate viral protease, initiating lytic cell death specifically within infected cells.

Using hepatitis A virus (HAV) as a proof-of-concept model, we substituted the native GSDMD cleavage site with the canonical 3C protease recognition motif to generate the corresponding VIDA. VIDA mRNA was formulated using clinically validated LNPs and administered intravenously in multiple mouse models.^8,9 VIDA mRNA treatment showed an excellent safety and efficacy profile in all experimental settings. Most importantly, single-cell transcriptomic profiling revealed that VIDA orchestrates a coordinated two-tiered antiviral response: direct elimination of infected cells plus profound remodeling of the hepatic immune landscape. We termed this the “kill-and-alert” mechanism. This dual-mode action distinguishes VIDA from conventional antivirals and underpins its curative potential.

A defining advantage of VIDA lies in its modular and flexible design. Swapping the viral protease recognition motif allows precise retargeting to distinct pathogens, enabling rapid adaptation. We further validated this versatility across three phylogenetically divergent viruses, HAV, Zika virus (ZIKV), and SARS-CoV-2, confirming broad-spectrum applicability. To further enhance precision and resilience against viral escape, we integrated the generative artificial intelligence (AI) model to predict and prioritize high-efficiency, low-off-target cleavage variants. This approach yielded multiple optimized VIDA mutants with substantially improved proteolytic kinetics compared with wild-type—establishing a scalable, AI-augmented framework for real-time therapeutic evolution against emerging variants.

Mechanistically, the VIDA strategy differs fundamentally from conventional antivirals that directly inhibit viral enzyme activity. By engineering host effector proteins, we transform viral proteases into a trigger for cell death, enabling precise elimination of infected cells. At the platform level, the modular design allows VIDA to be theoretically adapted to all viruses encoding specific proteases. The combination of the mRNA-LNP delivery and the AI-guided design ensures rapid production, fast iteration, and potent antiviral efficacy.

Beyond infectious diseases, this programmable platform holds translational potential for oncology. The modular architecture enables straightforward exchange of cleavage sequences to recognize proteases selectively upregulated in cancer cells, particularly in virus-associated malignancies such as Epstein-Barr virus (EBV)-positive post-transplant lymphoproliferative disorder (PTLD), where tumor cells may express the herpesviral assemblin protease BVRF2. Such re-engineered VIDA constructs could trigger tumor-restricted lytic cell death, harnessing the dual “kill-and-alert” function to eliminate malignant cells while converting immunologically “cold” tumors into inflamed, T cell-infiltrated lesions.¹⁰ For oncogenic viruses such as EBV and Kaposi sarcoma-associated herpesvirus (KSHV) that persist in a transcriptionally silent latent state within tumor cells, their lytic-cycle assemblin proteases are largely absent. VIDA would thus likely require co-administration of lytic-inducing agents (e.g., HDAC inhibitors or BZLF1/RTA mRNA) to force viral reactivation and thereby license protease-dependent VIDA activation. Alternatively, VIDA may be suited as a prophylactic or pre-emptive strategy in settings of active viral replication, such as preventing EBV-PTLD in high-risk seronegative transplant recipients or halting the progression of chronic active EBV infection to EBV-associated T/NK-cell lymphomas and Hodgkin lymphoma. In the context of frequent viral mutations and emerging infectious diseases, this virus-type-independent, rapidly designable mRNA strategy offers an entirely new paradigm for antiviral drug development and establishes a versatile framework expandable to cancer immunotherapy.

Acknowledgments

This work was supported by grants from the National Key Research and Development Program of China (2021YFC2302400 and 2025YFC2311802) and the National Natural Science Foundation of China (82350801). The figure was created with BioRender.com.

Declaration of interests

C.-F.Q. and Y.-J.H. have filed patents related to VIDA.