Experimental therapy could lead to one-size-fits-all antiviral drug

An experimental broad-spectrum antiviral therapy is described in Science Translational Medicine: a set of 10 interferon-inducible genes (ISGs) is delivered to cells via mRNA in lipid nanoparticles. This short-term “switching on” of antiviral proteins stopped the replication of viruses in cell culture and weakened the disease in hamsters and mice infected with influenza and SARS-CoV-2. The effect lasts for approximately 3-4 days and is intended as a tool for rapid protection against outbreaks of unknown viruses.

Background

Why a “universal” antiviral at all?
Classic drugs and vaccines usually target a specific virus and/or strain. This leaves a “hole” in the first weeks of outbreaks of new pathogens and when resistance appears. Therefore, there is growing interest in host-directed antivirals — drugs that turn on or adjust the host’s own defense pathways and thus provide a broad spectrum of action. Such approaches are potentially more difficult for virus mutations to bypass and may work until targeted drugs and vaccines are available.

Interferon protection and ISG are the cell's natural "shield".
Type I interferons trigger the expression of hundreds of interferon-induced genes (ISG), whose combined work suppresses the virus at different stages of the life cycle. For many ISG, the mechanisms are known (MxA, OAS/RNase L, IFIT, etc.), for some, they are still being studied, but the principle of the "multifactorial wall" is well-established. The idea of "temporarily turning on" the core of this program synthetically seems logical.

A human ‘nature experiment’: ISG15 deficiency.
Observations of people with inherited ISG15 deficiency suggested the central hypothesis of the new work: in human cells, the absence of ISG15 removes the inhibition of the USP18 regulator and leads to a prolonged IFN-I signal; such cells exhibit increased resistance to a number of viruses (in culture and primary cells). This differs from mice and highlights the species-specificity of the interferon network.

Why an mRNA “cocktail” of several ISGs?
Individual ISGs act on different nodes of the viral cycle; a combination of several genes theoretically provides an additive/synergistic barrier and reduces the chances of the virus “slipping through.” Precedents for the broad antiviral potential of individual ISGs have already been described, but parallel expression of “dozens” of key ISGs is an attempt to bring the cell closer to the physiological state of “interferon readiness” without systemic administration of IFN and its side effects.

Lung delivery: why it is difficult and relevant.
For respiratory viruses, local protection in the airways is optimal. Lipid nanoparticles (LNPs) are a proven platform for mRNA delivery, but the intranasal/inhalation route has special requirements: stability during aerosolization, passage through mucus and surfactant, “tuning” the composition (e.g. PEG-lipid) and route of administration. This has been actively studied in recent years.

How does this new work differ from previous efforts?
The authors in Science Translational Medicine assembled a multi-mRNA cocktail of 10 ISGs in a single LNP formula, administered it locally into the respiratory tract of rodents, and demonstrated a short-term (≈3–4 days) broad-spectrum “antiviral state” against influenza and SARS-CoV-2 — both prophylactically and with a therapeutic effect in the model. Conceptually, this is a bridge to the early days of the outbreak, while there is no specific therapy.

Limitations of the approach and questions for the future.
This is still preclinical (cells, mice, hamsters); optimization of delivery to the lungs, study of toxicology, frequency of "recharging" of protection without excessive inflammation and compatibility with the formation of adaptive immunity are needed. The host-directed field is actively developing, but requires a delicate balance of efficiency and safety.

An idea inspired by a rare immune defect

The basis is observations of people with ISG15 deficiency: their type I interferon pathway is chronically slightly activated, and their cells are surprisingly resistant to many viruses. Duchamp Bogunovic's team decided not to turn off ISG15 (which would have dozens of side effects), but to selectively "turn on" a dozen key ISGs that provide the main antiviral armor.

How the prototype works

• One lipid nanoparticle contains 10 mRNAs encoding selected ISGs.
• After entering the cells, they synthesize ten “guardians” of the innate immunity for several hours or days, creating a temporary antiviral state.
• Key idea: low dose and short expression → less inflammation than in people with the congenital ISG15 defect, but enough to keep the virus at bay.

What was shown in the work

• In vitro: protecting cells from various viruses; the authors “have not yet found a virus that would break through” such a barrier (caution: this is about cell culture).
• In vivo (rodents): when administered prophylactically as drops “into the lungs through the nose,” the drug reduced the replication and severity of the disease during influenza and SARS-CoV-2 infection.
• Duration: approximately 3-4 days of protection; the authors position this as a “bridge” for risk groups (medical workers, nursing homes, families of patients) in the first days of the outbreak.

Why is this important?

Most antiviral drugs and vaccines are specific to a single pathogen. The host-dependent gene approach offers the chance for a broad spectrum of action — even when the pathogen has not yet been identified. At the same time, temporary activation of innate protection does not interfere with the formation of memory (adaptive immunity) to the virus itself.

Limitations and open questions

• For now, this is pre-clinical: cells, mice, hamsters. There is still a way to go to reach people.
• Delivery to the lungs is a bottleneck: we need to improve the efficiency of nanoparticles getting to the right cells.
• Efficacy window and safety: how stable is the effect against different strains and families of viruses? How often can you "recharge" the defense without excessive inflammation?
• Conflicts of interest and IP: patent application for combination 10 ISG (Icahn School of Medicine at Mount Sinai) and author's involvement in startup Lab11 Therapeutics.

Context: Why does it "work" this way at all?

In humans with ISG15 deficiency, cells demonstrate an enhanced interferon response program and no increased vulnerability to viruses (unlike mice). These observations formed the basis of the hypothesis: by moderately and briefly turning on the “core” of interferon protection (10 ISG), it is possible to obtain a universal barrier without chronic inflammation.

What's next?

The authors call the technology a candidate for the “early days” of the next pandemic — a universal shield while the world develops targeted vaccines and drugs. The immediate steps are to optimize delivery, assess toxicology and duration of protection, and then discuss early human trials. Large-scale adoption will require independent replications and regulatory dialogue.

Source: Science Translational Medicine article (August 13, 2025) and Columbia University Medical Center press release. DOI: 10.1126/scitranslmed.adx57