The silica shell thickness, t shell , of the SPION@SiO 2 NPs was determined from TEM images, Fig. . It was observed that as the level of the experimental factors increased, the shell thickness of the particles also increased. Nanoparticles produced using lower levels of the factors (i.e. treatments 111 to 122) were observed to have an ultra-thin silica shell, however the particles themselves appeared embedded within a non-uniform aggregated silica matrix, lacking discrete individual core@shell structures. It is thought that when a lower number of moles of TEOS (0.16 mmol) and NH 4 OH (0.13 mmol) and fewer fractionated additions of TEOS are used, the formation of by-product silica is Fig. TEM images of SPION@SiO 2 NPs produced using conditions determined from the 3 factorial model, at level 1 of the number of moles of TEOS (0.16 mmol). Scale bar is 50 nm. The x-axis (row) is the number of fractionated additions of TEOS (Frac. Add. TEOS), which is increasing from left to right in levels of fractionated additions of TEOS, from levels 1 to 3. The y -axis (column) is the number of moles of NH 4 OH, and is increasing from top to bottom in levels 1 to 3 for the number of moles of NH 4 OH. The z-axis is the number of moles of TEOS. Each 3 digit code is the xyz coordinates for each treatment condition generated from the experimental domain, as described in Table . The remaining TEM images, at TEOS levels 2 and 3 can be found in Fig. , ESI †. Additionally, repeats of the centre point condition (treatment 222) can be found in Fig. , ESI †.