The Potential of Lipid Carriers With Sialidase mRNA Payloads as Broad-Spectrum Host-Directed Antivirals

Abstract

Sialic acid is a monosaccharide found on the surface of cells in the respiratory tract and plays a crucial role in immune regulation and cell signaling. It is present in 2 main forms: α(2,3)-linked and α(2,6)-linked, throughout the human respiratory tract, where α(2,6)-linked sialic acids are more abundant in the upper respiratory tract, and α(2,3)-linked sialic acids are more abundant in the lower respiratory tract. These different forms of sialic acid serve as entry receptors for different World Health Organization Priority Pathogens, including members of the Orthomyxoviridae and Coronaviridae family. Hence, targeted cleavage of sialic acid could serve as a potential prophylactic and therapeutic antiviral strategy by reducing the presence of sialic acid on the host cell surface, thereby preventing virion binding and cell-to-cell transmission of the virus. Previous research has developed an inhaled sialidase capable of transiently cleaving sialic acid in the respiratory tract. However, the short duration of protection offered, adverse side effects, and generation of anti-sialidase antibodies by the host hindered the efficacy of the therapeutic. In contrast, a mRNA-encoded sialidase could remain on the surface of the cell for longer periods of time, conferring more sustained and comprehensive sialidase activity and protection against viral entry. To deliver the mRNA payload, liposomes and lipid nanoparticle-based delivery systems have demonstrated effective surface expression of mRNA transcripts through different administration methods, such as inhalation and injections. Taken all together, this shows a promising avenue of host-directed antiviral therapy, where delivering sialidase mRNA via liposomes or lipid nanoparticles could act as a broad-spectrum host-directed antiviral strategy. However, key questions remain regarding the optimal neuraminidase mRNA to express, the range of viruses this antiviral strategy could be effective against, the potential cytotoxicity of expressing enzymatic proteins on the surface of cells, and the effects of sustained sialic acid removal. Further investigation is needed to assess the feasibility and safety of this approach.