Intranasal nanoparticle bite agonist with antiviral and immunomodulatory activity against SARS-CoV-2 variants.

In a recent study published in bioRxiv* Prepress Server Researchers have developed an immunomodulator, NanoSTING, and demonstrated its broad-spectrum antiviral properties in hamsters and mice.

Study: Intranasal nanoparticle bite agonist has broad protective immunity against respiratory viruses and variants. Image Credit: pinkeyes / Shutterstock

background

NanoSTING is a nanoparticle formulation of cyclic adenosine monophosphate (cGAMP), a potent natural immune vector. Researchers have shown that it broadly neutralizes several respiratory viruses, including drug-resistant strains of influenza A and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The inducer of the interferon gene (STING) pathway enables a broad innate immune response against viruses, including SARS-CoV-2. Mechanistically, STING activation involves type I and III interferons (IFN-I and IFN-III) and controls early SARS-CoV-2 infection in the upper respiratory tract.

There is an unmet medical need for prevention and early post-exposure treatments to prevent coronavirus disease 2019 (COVID-19) and reduce transmission of SARS-CoV-2. Although vaccines are the preferred and necessary means of protection against SARS-CoV-2, they are not sufficient to combat SARS-CoV-2 virus for several reasons, as follows:

i) The mutational plasticity of SARS-CoV-2 facilitates its evolution, and vaccines cannot be custom-made for each new variant.

2) Vaccines are distributed unfairly globally, making it impossible to immunize all humans.

iii) As with influenza, people will eventually stop taking extra booster doses that facilitate the spread of SARS-CoV-2.

4) Finally, but most importantly, vaccines can prevent transmission of COVID-19 but not transmission of SARS-CoV-2.

Similarly, monoclonal antibodies (mAbs) are expensive, given only in clinical settings, and largely ineffective against many SARS-CoV-2 variants, including Omicron. Oral antivirals, such as paxlovid and molnupiravir, are approved for use in humans but are susceptible to development and resistance to SARS-CoV-2.

Immunomodulators, such as defective interfering particles (DIPs), inhibit the replication of wild-type SARS-CoV-2 and have been shown to be effective in small animal models; However, these must be created for each virus individually. Similarly, defective viral genomes (DVGs) need to reproduce in vivo After giving limit their therapeutic potential. The problem with volatile interferons, such as IFN-α2b, is that the timing of its administration is critical to maximizing efficacy.

Complex lipid nanoparticles with defective genomes can alleviate all of the above concerns, and naturally occurring lipid component NanoSTING has already been tested in humans.

about studying

In this study, the researchers tested the effectiveness of a formulation of cGAMP nanoparticles, called NanoSTING, against multiple VOCs of SARS-CoV-2 in hamsters and influenza A in mice. They demonstrated the high translational potential of small amounts of NanoSTING. Notably, intranasal delivery of NanoSTING enabled the continuous release of cGAMP into the nasal compartment and lungs of test animals for up to 48 h, activating multiple antiviral pathways and facilitating IFN-I and IFN-III responses.

The team modified a spontaneously immortalized monocyte-like cell line (THP-1) and stimulated these cells with NanoSTING at a dose of 2.5-10.0 μg to confirm its ability to induce responses to interferon. They observed a low level of luciferase activity at six hours, and excretion was maximal at 24 hours with five micrograms and 10 micrograms of Nanosting. Furthermore, they performed kinetic measurements for 24 h by measuring luciferase activity in the supernatant.

Although cGAMP is a powerful natural activator of the STING pathway, it in vivo Half-life ~35 minutes. Therefore, the researchers administered varying amounts of NanoSTING (10-40 μg) intranasally to groups of BALB/c mice. Next, they harvested the nasal turbinates and lungs of the test mice. They performed a quantitative enzyme-linked immunosorbent assay (ELISA) for the cGAMP assay.

Similarly, the team investigated the effect of intranasal administration of NanoSTING on Syrian golden hamsters.

Results

Dynamic light scattering (DLS) analysis revealed that the NanoSTING has an average particle diameter of 98 nm, with a multiple scattering index of 25.1% and a zeta potential of -40 mV. Furthermore, the authors found that NanoSTING was immunologically active and remained stable even without refrigeration.

The authors observed a dose-dependent increase in cGAMP concentration in the nasal turbinates of test mice. At a dose of 10 mcg, cGAMP was detected for up to 12 hours to return to baseline at 24 h, while at higher doses (20-40 mcg), cGAMP was detected for up to 24 h and reversed at 48 h.

While in the lungs of mice, cGAMP could be detected at higher doses (20 and 40 mcg); However, it was not undetectable at any time point in the serum of test animals, even at a dose of 40 mcg. Together, these results confirmed that NanoSTING transported cGAMP into the nasal passages in a concentration and time-dependent manner without systemic exposure.

In the hamster model, the volume of transport for the liquid formulations of NanoSTING did not affect the biodistribution of the lung and nasal compartments.

Hamsters receiving 60 mcg of NanoSTING daily for four consecutive days showed no changes in clinical signs, such as temperature or body weight, compared to controls. In hamster lungs, NanoSTING efficiently engages both interferon-dependent and interferon-dependent antiviral pathways. in vivorelative interferon ratios (RIR) of 0.27 and 0.67 achieved a sufficient 50% and 100% reduction in SARS-CoV-2 titer, respectively, compared to the peak IFN responses observed with SARS-CoV-2 infection.

Conclusions

In the current study, a single dose of intranasal NanoSTING acted remarkably as a preventive and curative method against multiple respiratory viruses, including neutralization-resistant SARS-CoV-2 variants such as Omicron. Moreover, it conferred permanent protection against the highly pathogenic SARS-CoV-2 variants, alpha and delta, without the need for retreatment.

Overall, NanoSTING has demonstrated the potential to prevent respiratory viral diseases in susceptible populations. Therefore, it can be used for rapid intervention in respiratory infections long before the pathogen is identified.

*Important note

bioRxiv publishes preliminary scientific reports that are not subject to peer review, and therefore should not be considered conclusive, guide clinical practice/health-related behavior, or be treated as established information.

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