Abstract
Therapeutic mRNA delivery has been described for several treatment options, such as vaccination and cancer immunotherapy. However, mRNA delivery has to be accompanied by the development and testing of suitable carrier materials due to the instability of mRNAs in human body fluids. In the present study, we investigated the ability of recently developed Viromers to deliver mRNAs in a classical inflammatory setting. We tested mRNAs coding for active components of preclinical (7ND) and approved (sTNF-RII) biologics, in vitro and in vivo. 7ND is an established blocker of the CCR2 axis, whereas sTNF-RII is the active component of the approved drug Etanercept. Viromer/mRNA complexes were transfected into murine macrophages in vitro. Protein expression was analysed using Luciferase reporter expression and mainly identified in spleen, blood and bone marrow in vivo. 7ND-mRNA delivery led to efficient blockage of monocytes infiltration in thioglycolate-induced peritonitis in mice, underlining the ability of Viromers to deliver a therapeutic mRNA cargo without overt toxicity. Therefore, we propose Viromer-based mRNA delivery as a suitable option for the treatment of inflammatory disorders beyond infusion of biological molecules.
Highlights
Therapeutic mRNA delivery has been described for several treatment options, such as vaccination and cancer immunotherapy
Transient gene therapy includes the replacement of defective genes by the introduction of intact copies, or the inactivation of pathogenic gene products without a permanent change of the genetic code in somatic c ells[4]
Delivery was first analysed in cell culture using the mouse monocyte/macrophage cell line RAW264.7
Summary
Therapeutic mRNA delivery has been described for several treatment options, such as vaccination and cancer immunotherapy. We investigated the ability of recently developed Viromers to deliver mRNAs in a classical inflammatory setting. We tested mRNAs coding for active components of preclinical (7ND) and approved (sTNF-RII) biologics, in vitro and in vivo. We propose Viromer-based mRNA delivery as a suitable option for the treatment of inflammatory disorders beyond infusion of biological molecules. Synthetic mRNA is readily degraded in most biological fluids and a non-assisted delivery into cells is currently limited to local injections and directed mainly to dendritic c ells[6]. Lipid nanoparticles (LNPs) are used for delivery of mRNAs into somatic cells These cationic carriers, pegylated, interact with serum components or the complement system, and may induce undesired immune r esponses[7].
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