Design is the critical first step in the development of a new mRNA medicine. Informed sequence design can confer major improvements to the performance of mRNA medicines, including the strength and duration of protein expression. Here, we present mRNArchitect (https://basefacility.org.au/software/), an open-source software platform for the optimisation of primary mRNA sequences1. mRNArchitect enables the rapid assembly of mRNA sequences according to user-defined constraints, such as codon optimisation, secondary structure, GC content, and uridine depletion. mRNArchitect has been extensively validated across diverse mRNA applications in multiple cell and tissue types. Sequence optimisation with mRNArchitect increases protein expression by up to five-fold compared to alternative design methods, including software incorporating AI optimisation. We identify 5′ and 3′ untranslated region (UTR) sequences that increase protein expression by up to 40% relative to benchmark UTRs. Moreover, we show that mRNAs with stable secondary structures have improved stability, however, this is associated with initiation of the innate immune response via induction of TLR-3. This sequence optimisation approach is therefore likely to be more suitable for mRNA vaccines, due to the inherent adjuvanticity of the design, than for protein replacement therapies, which require repeat dosing. Finally, we show that incorporation of microRNA binding sites in 5′ or 3′ UTRs can decrease protein expression in off-target tissues by an order of magnitude while retaining strong expression in target tissues. Together, our results show how the levers of mRNA design can improve mRNA performance in different therapeutic contexts, establishing mRNArchitect as a robust and flexible framework for the optimisation of mRNA expression and tissue specificity.