The skin is the largest organ of the human body. It fulfills various functions, such as preventing the loss of salts and fluids as well as regulates the body temperature. In addition, the skin acts as a highly complex and effective biological barrier, hindering the penetration of harmful substances (feature mostly attributed to the stratum corneum; SC). Overcoming the SC represents a great challenge in dermal and transdermal therapies, leading to the development of multiple strategies to enable the permeation of therapeutics across the skin. Using penetration enhancers (chemical or physical) has proven to increase the penetration of therapeutics. Nevertheless, the use of penetration enhancers exposes a great risk, as they can lead to permanent damage on the skin, reducing its barrier efficiency and resulting in the intrusion of harmful substances, which can result in inflammation. Nanoparticle based dermal and transdermal drug delivery approaches represent promising tools to deliver drugs to the target site, while reducing or eliminating side effects. It has been found that soft nanoparticles can induce skin hydration and subsequently deliver therapeutics into the skin. Due to their high surface area, tunable sizes, easy functionalization (in situ or post-synthetic) and large encapsulation capacities, nanocapsules (NCs) represent a promising strategy for topical drug delivery. NCs are generally defined as hollow nanoparticles composed of a cross-linked shell surrounding a core forming space. Herein, we aim to synthesize soft thermoresponsive nanocapsules (tNCs) to induce skin hydration, thus enabling the skin penetration of high molecular compounds. For this purpose, NCs with a thermoresponsive shell and a void of 100 nm diameter, were synthesized. These NCs can shrink or swell upon a thermal trigger, which can be used to induce the release of water and or other encapsulated molecules in a controlled fashion. The tNCs were built using silica nanoparticles as sacrificial templates (to ensure the reproducibility or their core) in a seeded precipitation polymerization. Different ratios of poly(N-isopropylacrylamide) (PNIPAM) and poly(N-isopropylmethacrylamide) (PNIPMAM) were employed as thermoresponsive polymers and either N,N’-methylenebisacrylamide (BIS) as cross-linker or dendritic polyglycerol (dPG) as macrocross-linker were utilized to build the tNCs’ shell. Firstly, the effect of the synthesis on the mechanical properties of the tNCs was investigated. For this purpose, a comprehensive study was performed to investigate the mechanical properties of well-known (PNIPAM-BIS) thermoresponsive nanoparticles. In the study, nanogels, nanogels with a hard core and nanocapsules were investigated below and above the volume phase transition temperature (temperature at which the particles change from a swollen state to a collapsed state) (VPTT) using nanoparticle tracking analysis (NTA), cryogenic-electron microscopy/electron tomography, and atomic force microscopy (AFM) in liquid. It could be shown, that the different structure of the particles affects their thermoresponsive behavior. Moreover, outstanding thermomechanical changes were found for the NCs (Young modulus changes from kPa to GPa upon crossing the VPTT). These findings underline the importance of fully characterizing the particles as their thermomechanical properties could enhance or limit their further applications. Additionally, these results were used to rationally design novel tNCs to induce skin hydration using dPG to introduce non-thermoresponsive domains within the shell; thus, leading to flexible materials even above the VPTT. By varying the ratio between PNIPAM and PNIPMAM, the VPTT, as well as the shell density, could be controlled. Next, the interactions and effects of tNCs on the stratum corneum were investigated using fluorescence microscopy, high resolution microscopy, and stimulated Raman spectromicroscopy. It could be shown, that the thermoresponsive properties of the tNCs could increase skin hydration. Finally, the potential of the NCs as penetration enhancer was assessed by using Atto Oxa12 NHS ester (a high molecular weight dye) as a model drug. It could be demonstrated, that the NCs increased the penetration of Atto Oxa12 in comparison to an aqueous formulation and a solution of the dye in 30% DMSO. This thesis demonstrates that both material properties and core-nanoarchitecture can considerably affect the thermomechanical properties of soft nanoparticles. In addition, it could be proven that the dPG-based tNCs cause skin hydration and that their thermoresponsive features can further enhance the hydration of the skin. Moreover, this work underlines the outstanding potential of tNCs to act as penetration enhancers for high molecular weight compounds by inducing skin hydration.
