Lipid nanoparticles (LNPs) utilising ionisable lipids are a proven delivery vehicle for RNA cargo. However, while their safety has been demonstrated in widespread deployment globally, they exhibit increased toxicity in humans compared to the rodent models typically used in preclinical studies. This necessitates a considerable dose reduction when translating from mice to humans, even when standard interspecies dose scaling is applied. With this in mind, we adopted a rational design approach to conceptualise and synthesise novel ionisable lipids. Unlike combinatorial screening methods, our targeted approach achieved a high hit rate in producing mRNA-LNPs with acceptable physical characteristics and demonstrable in vivo activity in animal models. Subsequent stratification of the lipid candidates based on safety and efficacy identified a subclass of compounds with an improved safety profile while maintaining industry-standard activity in vaccine settings. In this presentation, we will describe our design strategy and highlight key findings that offer alternative options for researchers and developers working in the mRNA delivery space.