While SPION@SiO 2 NPs are a prominent area of research, there are still difficulties associated with the reverse microemulsion method. Mainly, the route produces a large fraction of noncore SiO 2 NPs, a non-magnetic by-product that requires additional processing to separate. Since reproducibility as well as particle size and morphology control are vital when considering such particles for biomedical applications, understanding the relationship between the reaction conditions and resulting SPION@SiO 2 NPs is critical. To date, optimisation of SPION@SiO 2 NPs has relied on 'one factor at a time' (OFAT) variation, where each experimental factor is changed individually. Consequently, a narrow range of the experimental domain is typically examined and variable interactions overlooked. This limits the understanding of how experimental variables affect the outcome of a synthesis, often leading to inaccurate conclusions and sub-optimal results. Design of experiment (DoE) is a powerful statistical tool for understanding and optimising the relationship between the experimental variables and the outcome of a process. The use of DoE for nanoparticle synthesis is gaining popularity and has provided insight into reaction mechanisms. For example, Lak et al. have used a DoE approach for the optimisation of SPIONs, with tailorable magnetic properties. In two separate studies, interactions were identified between experimental factors responsible for determining the dispersity and magnetisation of SPIONs formed via thermal decomposition and non-hydrolytic synthesis. Similarly, Roth et al. have employed DoE to study the formation of SPIONs using co-precipitation. The magnetisation of the SPI-ONs was deemed highly dependent on the experimental variables used, such as the molar ratio and concentration of Fe 2+ /Fe 3+ ions. Arafa et al. used DoE to tune the properties of pregabalinloaded niosomes for therapeutic delivery. This was made possible by examining the combined effect of different factors simultaneously. There have been several successful examples of the optimisation of nanoparticle synthesis and maximising their functionality using a DoE approach in the literature. While DoE has proved a powerful tool for nanoparticle optimisation, this approach has not been applied in the context of SPION@SiO 2 NP synthesis. Herein, we applied a statistical approach to understand and predict the influence experimental factors have on the properties of SPION@SiO 2 NPs formed via a reverse microemulsion method. The number of moles of the reactants NH 4 OH and TEOS, as well as the number of fractionated additions of TEOS were selected for investigation (vide infra 2.4 and 3.2). The size and stability of SPION@SiO 2 NPs formed were characterised using transmission electron microscopy (TEM) and dynamic light scattering (DLS). Magnetic properties were evaluated using vibrating sample magnetometry (VSM). The experimental campaign was designed using a 3 3 full-factorial design and modelled using a response surface model (RSM) and analysed via the software JMP. In this way, we aim to provide a comprehensive understanding of the influence of important preparation parameters on resulting SPION@SiO 2 NPs, and predictive capability to produce optimal single-core@shell particles.