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DNAzymes are a group of synthetic nucleic acid based APIs that have the ability to inhibit protein translation by targeting the transcript of a specific gene. DNAzymes have already been tested in clinical trials with five different diseases. Two of the DNAzymes have been tested for dermal application against atopic dermatitis and skin cancer (squamous-cell carcinoma, basal cell carcinoma). The development of an appropriate dermal drug delivery system (DDS) is challenging, because DNAzymes are prone to enzymatic degradation and have problematic properties in terms of skin penetration. The task of this thesis was to develop a dermal DDS that addresses both issues. The dermal DDS should maintain the integrity of DNAzymes while enhancing the penetration and uptake of DNAzymes into human skin and the targeted keratinozytes. First, to ensure the integrity of this particularly group of APIs, the degradation of DNAzymes on human skin had to be identified and analysed. The analysis revealed that unprotected DNAzymes were rapidly degraded by a DNase II like activity. Therefore, protective systems were developed to protect against DNase II. Especially, complexation of DNAzymes with polycations, forming polyplexes, was able to sufficiently maintain the integrity of the API. Depending on the properties of the polycations a specific ratio (ξ) between the oppositely charged DNAzymes and polycations was necessary to fully protect. A ξ-ratio of about 1 2 along with a positive zeta potential increased in general the chances of an appropriate protection. The most effective protection was achieved with polycations of biodegradable chitosan. To enhance the penetration of DNAzymes through the skin barrier the submicron emulsion (SME) was identified as ideal candidate and the SME was developed as carrier system for DNAzymes. The SME increased the penetration of API into skin. The DNAzymes accumulated especially in the stratum corneum due to the SME’s excipients. Consequently, the stratum corneum was able to act as an API reservoir. The SME and the chitosan polyplexes were finally combined to a so called protective dermal DDS. The protective dermal DDS enhanced the penetration into the skin and protected the DNAzymes. On cellular level the uptake of DNAzymes into the targeted keratinocytes were enhanced due to the polyplexes.