ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2024
A Novel Self-Amplifying mRNA with Decreased Cytotoxicity and Enhanced Protein Expression by Macrodomain Mutations.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed.
- Self-amplifying RNA (saRNA) and circular RNA (circRNA) vaccines: Progress, evidence gaps, and translational pathways for durable and scalable immunization.Human vaccines & immunotherapeutics · 2026Review
- Bioengineering strategies for improving the immunogenicity of mRNA vaccines.Signal transduction and targeted therapy · 2026Review
- mRNA lipid nanoparticle vaccines: current status, challenges and future prospects.Molecular biomedicine · 2026Review
- Alphavirus replicase and regulatory RNA elements in host interactions and viral vector engineering.Journal of virology · 2026Review
- Status and outlook of mRNA therapeutics for viral diseases.EMBO molecular medicine · 2026Review
- Impact of pre-existing anti-replicase immunity on the efficacy of self-amplifying mRNA vaccines.Nature communications · 2025Article
- mRNA vaccine platforms and novel delivery systems: From mechanistic principles to clinical translation.Human vaccines & immunotherapeutics · 2025Review
- Advances in RNA-based cancer therapeutics: pre-clinical and clinical implications.Molecular cancer · 2025Review
- Advancements and challenges in next-generation mRNA vaccine manufacturing systems.Clinical and experimental vaccine research · 2025Review
- Review
- The Interplay Between Therapeutic Self-Amplifying RNA and the Innate Immune System: Balancing Efficiency and Reactogenicity.International journal of molecular sciences · 2025Review
- Article
- Co-expression of HSV-1 ICP34.5 enhances the expression of gene delivered by self-amplifying RNA and mitigates its immunogenicity.FEBS open bio · 2025Article
- The advent of clinical self-amplifying RNA vaccines.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Controlling reactogenicity while preserving immunogenicity from a self-amplifying RNA vaccine by modulating nucleocytoplasmic transport.NPJ vaccines · 2025Article
- Self-Amplifying RNA: Advantages and Challenges of a Versatile Platform for Vaccine Development.Viruses · 2025Review
- A Novel Self-Amplifying mRNA with Decreased Cytotoxicity and Enhanced Protein Expression by Macrodomain Mutations.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
Corrections and comments
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The efficacy and safety of self-amplifying mRNA (saRNA) have been demonstrated in COVID-19 vaccine applications. Unlike conventional non-replicating mRNA (nrmRNA), saRNA offers a key advantage: its self-replication mechanism fosters efficient expression of the encoded protein, leading to substantial dose savings during administration. Consequently, there is a growing interest in further optimizing the expression efficiency of saRNA. In this study, in vitro adaptive passaging of saRNA is conducted under exogenous interferon pressure, which revealed several mutations in the nonstructural protein (NSP). Notably, two stable mutations, Q48P and I113F, situated in the NSP3 macrodomain (MD), attenuated its mono adenosine diphosphate ribose (MAR) hydrolysis activity and exhibited decreased replication but increased payload expression compared to wild-type saRNA (wt saRNA). Transcriptome sequencing analysis unveils diminished activation of the double-stranded RNA (dsRNA) sensor and, consequently, a significantly reduced innate immune response compared to wt saRNA. Furthermore, the mutant saRNA demonstrated less translation inhibition and cell apoptosis than wt saRNA, culminating in higher protein expression both in vitro and in vivo. These findings underscore the potential of reducing saRNA replication-dependent dsRNA-induced innate immune responses through genetic modification as a valuable strategy for optimizing saRNA, enhancing payload translation efficiency, and mitigating saRNA cytotoxicity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.