| Summary: | The increasing development of resistance of <i>Candida</i> species to traditional drugs represents a great challenge to the medical field for the treatment of skin infections. Essential oils were recently proposed to increase drug effectiveness. Herein, we developed and optimized (2<sup>3</sup> full factorial design) Mediterranean essential oil (<i>Rosmarinus officinalis</i>, <i>Lavandula</i> x <i>intermedia</i> “Sumian„, <i>Origanum vulgare</i> subsp. <i>hirtum</i>) lipid nanoparticles for clotrimazole delivery, exploring the potential synergistic effects against <i>Candida</i> spp. Small sized nanoparticles (<100 nm) with a very broad size distribution (PDI < 0.15) and long-term stability were successfully prepared. Results of the in vitro biosafety on HaCaT (normal cell line) and A431 (tumoral cell line), allowed us to select <i>Lavandula</i> and <i>Rosmarinus</i> as anti-proliferative agents with the potential to be used as co-adjuvants in the treatment of non-tumoral proliferative dermal diseases. Results of calorimetric studies on biomembrane models, confirmed the potential antimicrobial activity of the selected oils due to their interaction with membrane permeabilization. Nanoparticles provided a prolonged in vitro release of clotrimazole. In vitro studies against <i>Candida albicans</i>, <i>Candida krusei</i> and <i>Candida parapsilosis</i>, showed an increase of the antifungal activity of clotrimazole-loaded nanoparticles prepared with <i>Lavandula</i> or <i>Rosmarinus</i>, thus confirming nanostructured lipid carriers (NLC) containing Mediterranean essential oils represent a promising strategy to improve drug effectiveness against topical candidiasis.
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