Viscosity of concentrated mRNA solutions: Implications for downstream processing

Messenger RNA (mRNA) therapeutics can be used to protect against infectious disease and for the treatment of cancers and genetic disorders. In order to obtain the desired therapeutic dosage, it is necessary to concentrate the mRNA to levels where the viscosity of the mRNA solutions can become significant. However, there is currently no quantitative data on the viscosity of these concentrated mRNA solutions. Experiments were performed with two model mRNA constructs: a firefly luciferase (Fluc) mRNA (2.117 kb) and a self-amplifying RNA (9.442 kb) over a wide range of concentrations. The viscosity of the larger saRNA was more than 140 mPa·s at a concentration of 28 mg/mL, which is more than 10× larger than that for the Fluc mRNA under the same conditions. The viscosity was a weak function of shear rate (from 10 to 100 s⁻¹), with some shear-thinning behavior. The viscosity data were analyzed using several available models from the literature, providing additional insights into the underlying physical behavior. The potential implications of the mRNA viscosity in the downstream processing of mRNA therapeutics are also discussed.