###### Abstract  
Titanium dioxide (TiO\({}_{2}\)) nanoparticles (NPs) are the subject of numerous studies and controversies on the risks they could pose to the environment and human health. When in contact with biological tissues, NPs can sometimes be challenging to precisely localize within subcellular structures (typically around 0.1 \(\upmu\)m) when they exist as isolated NPs, particularly when using the SIMS approach. Indeed, the chemical signals produced by isolated NPs are very low, so they can be confused with background signals. This was the motivation behind our development of a new strategy for correlating TEM/SIMS to detect TiO\({}_{2}\) NPs in close proximity to cutaneous correcocytes. For this purpose, we initially developed a new tool for TEM and SIMS image registration based on a non-rigid image-deformation-enabling image overlay. Combining SIMS and TEM data through this overlay enhances NP localization's precision. Secondly, we developed an algorithm based on the statistical analysis of multiplane SIMS images to denoise them. As a result, background noise was reduced, illuminating the low yet specific signals from isolated NPs. Finally, this new correlative approach enables the precise 3D localization of isolated NPs within the analyzed volume. We consider this method a breakthrough for subcellular-scale NP localization. TEM; SIMS; correlation; image registration; SCP filter; nanoparticles; titanium dioxide; skin Article The High Resolutive Detection of TiO\({}_{2}\) Nanoparticles in Human Corneocytes via TEM/NanoSIMS  
[PERSON], [PERSON], [PERSON]. Transcutaneous studies have revealed the passage of NPs through different layers of the skin [18; 19] without precising their location in different tissues. There are different experimental approaches to address the penetration or non-penetration of NPs. Imaging methods are more interesting approaches to detect and localize TiO\({}_{2}\) NPs in tissues. These methods include, for example, electron microscopy [9; 20; 21; 22] or SIMS [16]. With time-of-flight-SIMS, it is possible to detect and localize titanium from TiO\({}_{2}\) NPs but impossible to link their location to morphological structures, such as hair follicles or sebaceous glands [16]. In order to precisely localize NPs (or biomolecules, atoms, and sometimes their isotopes) close to (or in) biological structures, a commonly encountered strategy is a combination of a high-resolution technique with an analytical technique. A large list of combinations includes the following: mass spectrometry imaging and magnetic resonance imaging [23]; multiphoton tomography with fluorescence lifetime imaging microscopy [24]; TEM and SEM/EDX (scanning electron microscopy/electron dispersive X-ray spectroscopy) [14]; stimulated emission depletion and SIMS [25]; TEM and confocal microscopy [26]; electron microscopy and SIMS [27; 28; 29; 30; 31; 32; 33; 34; 35]; or even more techniques, such as autoradiography, SIMS and TEM [36], TEM, fluorescence microscopy, and SIMS [37; 38]; or EDX, electron energy loss spectroscopy, cathodoluminescence, and SIMS [39]. Such strategies have been used to study TiO\({}_{2}\) NPs using PIXE/RBS/STIM (particle-induced X-ray emission/Rutherford backscattering spectrometry/scanning transmission ion microscopy) [15; 17; 40; 41] or PIXE/RBS/STIM with TEM [10; 12], SEM [42], or autoradiography [13], or using secondary electron and mass spectral imaging in a gas field ion microscope [43; 44; 45]. Whatever the combination, it is important to adapt sample preparation to the physics and constraints of each instrument and to develop data analysis and correlation tools. For example, in [PERSON] et al. (2008) [10], TEM observations required ultra-fine sections (50-100 nm), whereas PIXE/STIM/RBS observations required semi-fine sections (500 nm). These authors pointed out differences in measurements (making interpretations difficult) that they attributed in large part to sample preparation. Combining data from various microscopy techniques can be achieved in several ways.