The skin is the largest organ of human body implicated in vital physiological and immunological processes, including protection against injury, infections, and environmental exposures. Nevertheless, a number of negative external and internal factors, including increased pollution along with modern lifestyle can significantly influence on the skin immunity, promote aging and reduce regenerative capabilities. Cosmetic formulations based on natural ingredients, including plant and marine/algae extracts, and microbial-derived bio-actives may help to maintain healthy skin condition and protect its beautiful appearance. The ImmunatuRNA®* (*The trademark ImmunatuRNA® is a registered trademark in the European Union EUTM 018365297 and Great Britain UK00003630172. Any reference to the registration of the ImmunatuRNA® trademark applies to the designated territories), a signature complex (VRFD SA/VERDILAB Switzerland) based on the Natural RNA molecules obtained from yeasts, with added marine exopolysaccharides and natural hyaluronic acid with potential benefits for antibacterial and antiradical defense and maintaining skin detox homeostasis. Therefore, the main aim of this study is to experimentally assess the ImmunatuRNA® complex capabilities to enhance natural skin antioxidant defenses and protection against oxidative stress, by using human fibroblast cell culture. Additionally, this study will investigate the effects of the skincare products with added ImmunatuRNA® complex on the skin microbiome composition in the group of healthy adults with various skin types. The results obtained from the in vitro studies consistently demonstrated that treatment with an ImmunatuRNA® complex protects human fibroblasts against exposure to pro-oxidants, while at the same time enhances anti-oxidative defenses of these cells, demonstrated as reduced formation of free radicals and upregulation of SIRT-1 protein. Furthermore, the cosmetic intervention carried on the group of 10 healthy human volunteers with different skin types (oily, dry, combined, normal) aged between 23 and 65 years old demonstrated that using interchangeably of two cosmetic products-a Natural Moisturizer Probiotic Cream and Natural Detox Replenishing Face Mask containing the ImmunatuRNA® complex, for 4-weeks led to favorable changes in the composition of skin microbiome observed as a reduction of relative abundance of adverse microorganisms, previously linked to the skin inflammation and infections, such as Citrobacter koseri, Bacillus spp., Enterococcus spp., Alcaligenes spp., Pantoea spp. and Staphylococcus aureus. Based on following results, the use of skincare products containing the ImmunatuRNA® complex can help maintain a healthy skin microbiome while possibly preventing against infections and negative environmental exposures, in particularly against oxidative stress in healthy adults with all types of skin with age range 23-65 years old.