Staphylococcus aureus (S. aureus) is a major causative agent of superficial and invasive skin and soft tissue infections. The occurrence of resistant S. aureus infections is a global healthcare concern reflected in poor treatment outcomes, long hospital stays and huge financial burden. During the infection establishment, S. aureus cell-to-cell communication process, called quorum sensing (QS), regulates the virulence factors production and formation of antibiotic resistant biofilms via the secretion of highly specific autoinducing signal molecules (AIs). TARDIS will develop innovative antimicrobial nano-enabled hydrogel scaffolds containing targeted systems with i) high bactericidal efficacy towards the pathogenic S. aureus and ii) ability to restore the beneficial microbiome balance and consequently the physiological functions of the skin. New antimicrobial marine-derived lipids and peptides will be employed for production of novel stand-alone nanoparticles with low potential for resistance development. These nano-vehicles will be incorporated into stimuli-responsive hydrogel-based 3D networks, for “on demand” delivery of the antimicrobial natural actives to the site of infection, avoiding toxic effects on human cells and beneficial skin microbiome. Taking advantage of the natural cell-cell communication principles, AIs and QS inhibitors (QSI) specifically interacting with S. aureus will be incorporated onto the surface of the developed nano-bactericides for targeted killing of the pathogen, reducing the side effects on human cells and skin microbiome. The antimicrobial efficacy and specificity of the nano-enabled hydrogels will be validated in vitro and in vivo. The treatment potential and effect of the skin microbiome balance will be further assessed by metagenome analysis, and the nano-safety of the developed antibacterials will be evaluated in accordance with OECD test guidelines.