Superparamagnetic iron oxide nanoparticles (SPIONs) have been extensively researched due to their unique magnetic properties when compared to bulk iron oxide including: superparamagnetic behaviour with a large magnetic susceptibility; low Curie temperature; and high coercivity. SPIONs are inverse spinel type iron oxide nanoparticles (NPs) including Fe 3 O 4 (magnetite) and γ-Fe 2 O 3 (maghemite) and are typically below 20 nm in size. The distinctive properties of SPIONs have made them useful for a range of applications in catalysis, purification, and biomedicine. Most notably, these materials have shown excellent potential in biomedical diagnostic and therapeutic applications including, but not limited to, point-of-care diagnostics, magnetic resonance imaging contrast agents, hyperthermic cancer treatments, and targeted drug delivery. Synthetic pathways to SPIONs are diverse, including co-† Electronic Supplementary Information (ESI) available: Tables and figures containing DoE experimental factors and response variables, lack of fit test for population of SPION@SiO 2 , SPION TEM and χ m , TEM images at Level 2 TEOS, TEM images at Level 3 TEOS, TEM at treatment 222, box-plot of size distribution of the measured NP diameter from TEM analysis (d TEM ) of all treatments, size distribution of validation experiments, mass susceptibility (χ m ) of all treatments. See DOI: 00.0000/00000000. precipitation, hydrothermal or thermal decomposition, solvothermal, and sol-gel reactions, with choice of reaction depending on the desired particle size, shape, hydrophilicity/phobicity and surface functionalities. As the magnetic properties of SPIONs are dependent on their size and shape, control of such properties, as well as uniformity of SPIONs, is critical. This is particularly imperative for biomedical applications, where highly polydisperse SPIONs can result in variable net magnetisation, leading to unreliable and poorly reproducible diagnostic and therapeutic capabilities. Co-precipitation of Fe 2+ /Fe 3+ salts is one of the most popular methods due to its high yield and low cost of manufacture; however, this typically produces SPIONs that are highly polydisperse, often with poor control over particle morphology, crystallinity, and aggregation. In contrast, thermal decomposition has greater control over size and morphology, generating monodisperse NPs with high crystallinity. In this approach, an organic-iron precursor is heated in situ with an amphiphilic surfactant or ligand such as oleic acid, a hydrophobic fatty acid, forming hydrophobic coated SPIONs which typically avoid aggregation. To obtain biocompatible SPIONs that are colloidally and physically stable, it is necessary to coat and functionalise the nanoparticle surface. Without this coating, the poor colloidal stability of SPIONs often leads to agglomeration under physiological conditions, leading to increased toxicity via red blood cell damage and haemolysis. Furthermore, uncoated SPIONs are susceptible to oxidation, which can contribute to changes in magnetic properties and chemical behaviour. There are various coating strategies to achieve this, including both covalent and noncovalent synthetic methods such as: surface stabilisation with cit-ric acid; capping with oleic acid; adsorption of polymers; or coating with inorganic material, such as silica (SiO 2 ). The latter is of particular interest as SiO 2 coated SPIONs are able to undergo subsequent surface modification with a variety of silanes or ligands due to readily modifiable silica chemistry. This provides the opportunity for functionalisation with an array of molecules such as fluorescent dyes, bio-compatible, biological or targeting ligands. There are several coating routes to attain SPION@SiO 2 core@shell NPs, with the option of either a non-porous or a mesoporous silica shell, the latter providing an opportunity to utilise the pores for cargo storage and release. Both sol-gel and reverse microemulsion routes are popular methods for the synthesis of non-porous SPION@SiO 2 NPs. The sol-gel method typically uses hydrophilic, small moleculestabilised, magnetic nanoparticles which are usually prepared by co-precipitation. Seeds of SiO 2 form on the SPION surface in-situ and grow through a Stöber mechanism under relatively mild conditions. However, SPION@SiO 2 NPs prepared using this route tend to have high polydispersity and poor control over morphology, often exhibiting multiple SPION cores within a single shell. Additionally, high yields of by-product SiO 2 , with no SPION core, are often observed. Enhanced control over morphology and reduced polydispersity can be achieved using a reverse microemulsion route. In this approach, hydrophobic magnetite (usually oleic acid stabilised) is dispersed in a nonpolar solvent (such as cyclohexane) along with a surfactant, e.g. IGEPAL-co-520, leading to ligand exchange. Ammonium hydroxide (NH 4 OH) and tetraethyl orthosilicate (TEOS) are added to the organic solution, forming a water-in-oil (w/o) emulsion. The SiO 2 precursor nucleates within the aqueous domain and forms around the SPION core generating SPION@SiO 2 core@shell NPs (Fig. ). In comparison, this approach has been reported as more favourable in terms of forming single core SPION@SiO 2 NPs with controlled shell thickness.