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.
Publication: CELL
http://dx.doi.org/10.1016/j.cell.2026.06.031
Author:
Lin Li
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China
School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China
Xiu-Li Yan
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China
State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China
State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China
Yan Fu
State Key Laboratory of Mathematical Science, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100190, China
State Key Laboratory of Agrobiotechnology, AoE Centre for Plant Vacuole Biology and Biotechnology, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China
State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China
Corresponding author
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China
Corresponding author
附件下载：
