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Antiviral therapy in a macrophage disguise
Monkeypox virus causes localized ulcers or pustules in the skin and mucous membranes that contain replicating virus and serve as the primary source of transmission. Active viral replication in these regions induces a large inflammatory response, contributing to tissue damage and disease severity. Current treatments involve painkillers, antivirals that are not specific for monkeypox, and patient isolation. Therefore, recent outbreaks have heightened the demand for antiviral therapy that could reduce disease severity and pathogen spread. Targeted photothermal therapy could be the answer! This technology utilizes nanoparticles to convert light into heat, effectively targeting cancer cells 1-3 and viral pathogens 4, which are more sensitive to high temperatures than healthy cells.
Using this technology, Li et al., encompassed nanoparticles within a macrophage membrane because the macrophage lining would bind to extracellular virus and bring the nanoparticle within close proximity to a pathogen. Then with localized light exposure, the nanoparticle would generate enough heat to kill the nearby virus without affecting the surrounding, healthy cells. Here, they tested this technology against vaccinia virus (closely related to monkeypox virus and less dangerous to handle) with the implication it could also be used against monkeypox virus.
Generation of Nanoparticles
To generate this nanoparticle, the authors chose a photothermal molecule, TPE-BT-DPTQ, that would produce heat upon 808 nm light exposure. This molecule was encapsulated in a poly (lactic-co-glycolic acid) or PLGA polymer to form the core. The core was mixed with extracted macrophage membranes to form the nanoparticle. The authors found an increase in nanoparticle size and surface potential, which indicated successful generation of the nanoparticle within the macrophage lipid bilayer. Thereby, the macrophage lining would bind to extracellular virus and upon localized light exposure, the nanoparticle would generate enough heat to eliminate the virus.
Validation of nanoparticles as a potential antiviral therapy
To test this novel nanoparticle, the researchers exposed the nanoparticle suspension to light and found the solution reached 70℃ within 7 minutes. This is a higher temperature than human skin which is around 33-39℃. In addition, the heating capabilities of the nanoparticles sustained 8 light cycles. This indicates the nanoparticles and their activity are quite stable and this could be beneficial if multiple rounds of therapy are needed to achieve virus clearance. Since a macrophage membrane was chosen as the outer coat to increase virus binding, the authors mixed the nanoparticles with vaccinia virus and found their interaction occurred within 2 minutes. Therefore, the macrophage membrane was a great method to bring the photothermal molecule in close enough proximity to directly target viruses. However, the authors wanted to ensure that the heat generated by the nanoparticle wouldn’t kill healthy cells. To test for this, they mixed the nanoparticles with uninfected cells and treated with light illumination. The therapy didn’t lead to cell death or an induction of pro-inflammatory markers(IL-1, IL-6, and C-GSF). This indicated the technology is safe for healthy cells and a promising antiviral therapy candidate.
Exploring the capabilities of nanoparticles with a mouse model of vaccinia virus disease
The next step in developing a novel antiviral therapy is testing the efficacy in a mouse model. The authors infected the tails of mice with vaccinia virus and at 7 days post infection, injected the tails with the nanoparticle solution. Then the tails were exposed to laser illumination for 10 minutes and the wound was analyzed 7 days later for signs of disease such as scab weight, viral burden, tissue histology, and pro-inflammatory cytokine production. All of these disease markers were reduced in mice treated with the nanoparticles and exposed to light, suggesting the nanoparticles are efficacious in their antiviral activity and promote wound healing. Given how contagious vaccinia and monkeypox virus infections are, the authors measured the ability of the photothermal therapy to prevent virus spread. They found that disease severity was drastically reduced in mice exposed to treated wound samples compared to their untreated wound controls. Therefore, this therapy not only reduced disease outcomes in infected mice but also diminished virus spread to others, thereby controlling two key characteristics of monkeypox virus outbreaks.
Conclusions
The authors successfully generated a nanoparticle with a photothermal molecule encompassed by a macrophage membrane. This nanoparticle was capable of targeting extracellular virus and upon light exposure, generated enough heat to eliminate replicating virus without affecting surrounding tissue. This therapy led to a decrease in localized disease markers and an inability of the highly contagious pathogen to spread to other mice. Overall, this study pushed a novel, minimally invasive antiviral therapy forward and opened the door for the development of future non-invasive methods to control viral disease and spread.
Additional Sources
1. Sagnik Nag and Oishi Mitra and Garima Tripathi and Israrahmed Adur and Sourav Mohanto and Muskan Nama and Souvik Samanta and BHJGaVSaV. Nanomaterials-assisted photothermal therapy for breast cancer: State-of-the-art advances and future perspectives. Photodiagnosis and Photodynamic Therapy. 2024;45:103959. doi: https://doi.org/10.1016/j.pdpdt.2023.103959.
2. Liu X, Zhou W, Wang T, Miao S, Lan S, Wei Z, Meng Z, Dai Q, Fan H. Highly localized, efficient, and rapid photothermal therapy using gold nanobipyramids for liver cancer cells triggered by femtosecond laser. Scientific Reports. 2023;13(1). doi: 10.1038/s41598-023-30526-x.
3. Liu Y, Zhu X, Wei Z, Feng W, Li L, Ma L, Li F, Zhou J. Customized Photothermal Therapy of Subcutaneous Orthotopic Cancer by Multichannel Luminescent Nanocomposites. Advanced Materials. 2021;33(30):2008615. doi: 10.1002/adma.202008615.
4. Labouta HI, Hooshmand N, Upreti T, El-Sayed MA. Localized Plasmonic Photothermal Therapy as a Life-saving Treatment Paradigm for Hospitalized COVID-19 Patients. Plasmonics. 2021;16(4):1029-33. doi: 10.1007/s11468-020-01353-x.
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