Protein replacement therapy entails the administration of an endogenous protein to compensate for a missing, defective or insufficiently expressed protein. Both direct replacement of the missing protein, as well as gene therapy, are possible approaches for the replacement of the protein of interest. Nonetheless, both these approaches face several shortcomings, such as a short half-life for the former, and a lack of dose adjustment options, as well as a risk of genomic integration, for the latter method. The use of (sa)-mRNA for protein replacement therapy poses several advantages, such as dose flexibility, prolonged protein expression, low-cost production, and no risk of genomic integration. We discovered that using proprietary cationic polymers for the delivery of (sa)–mRNA leads to a prolonged reporter expression in vivo, indicating that these polymers show potential in the context of protein replacement applications. In this project, we will further optimize the polymer design for prolonged protein expression and perform an in vivo proof-of concept study for protein replacement therapy.