Among polymeric nanocarriers, nanogels are especially promising non-irritating delivery vehicles to increase dermal bioavailability of therapeutics. However, accurately tailoring defined interactions with the amphiphilic skin barrier is still challenging. To address this limited specificity, we herein present a new strategy to combine biocompatible nanogels with the outstanding skin interaction properties of sulfoxide moieties. These chemical motifs are known from dimethyl sulfoxide (DMSO), a potent chemical penetration enhancer, which can often cause undesired skin damage upon long-term usage. By covalently functionalizing the nanogels' polymer network with such methyl sulfoxide side groups, tailor-made dermal delivery vehicles are developed to circumvent the skin disrupting properties of the small molecules. Key to an effective nanogel-skin interaction is assumed to be the specific nanogel amphiphilicity. This is examined by comparing the delivery efficiency of sulfoxide-based nanogels (NG-SOMe) with their corresponding thioether (NG-SMe) and sulfone-functionalized (NG-SO2Me) analogues. We demonstrate that the amphiphilic sulfoxide-based NG-SOMe nanogels are superior in their interaction with the likewise amphipathic stratum corneum (SC) showing an increased topical delivery efficacy of Nile red (NR) to the viable epidermis (VE) of excised human skin. In addition, toxicological studies on keratinocytes and fibroblasts show good biocompatibility while no perturbation of the complex protein and lipid distribution is observed via stimulated Raman microscopy. Thus, our NG-SOMe nanogels show high potential to effectively emulate the skin penetration enhancing properties of DMSO without its negative side effects.