Background/Objectives: Vine leaves are a bulky by-product that are disposed of and treated as waste in the wine production process. In the present study polyphenols from vine leaves were extracted and simultaneously encapsulated in a new delivery system consisting of liposomes and cyclodextrins. This system was further combined with propolis polyphenols encapsulated in cyclodextrins, resulting in a colloidal suspension for the release of antioxidants in a time-controlled way, the rate of which depends on the ratio of the materials. The result is a raw material that exhibits antioxidant and ECM protective effects when administered in skin fibroblasts (NHDFs). Methods: The antioxidant and ECM promoting efficacy of the produced raw material was assessed by the Folin–Ciocalteu method, DPPH assay, and in cellulo assays in fibroblasts, such as the cell viability assay, scratch assay, cell migration assay, gene expression analysis, and immunofluorescence analysis, for the detection, visualization, and quantification of collagen-I, collagen-IIIa, and elastin signals and collagenase assay. Results: Treatment of NHDFs with the combinatorial delivery system promoted collagen and elastin synthesis and deposition in normal conditions and, upon induced external stress, as assessed by in vitro transcriptomic and proteomic analysis. A significant inhibition of collagenase was also observed, suggesting a multitargeted efficacy of the active ingredients also by preventing collagen degradation. Conclusions: Therefore, this liposome–cyclodextrin encapsulated polyphenol complex represents a novel bioactive ingredient with promising skin applications.

Acne is a highly prevalent skin condition with multifactorial pathophysiology, where Cutibacterium acnes (C. acnes) overgrowths generate inflammation. C. acnes can grow and adhere, through the formation of biofilms, to almost any surface, which enables chronic infections. Acne treatment with antibiotics can induce topical antimicrobial resistance, impair microbiome biodiversity and cause cutaneous dysbiosis. In this study, we assess the effect of a standardized propolis extract (PE) from Greece against C. acnes, whilst maintaining skin’s microbiome biodiversity, and we investigate its effect against genes related to the attachment and colonization of C. acnes, as well as against biofilm formation. The extract has been chemically characterized by GC-MS and was additionally tested for its antioxidant properties by the Folin–Ciocalteu method and the 2,2-Diphenyl-1-Picrylhydrazyl (DPPH) assay and its regulatory activity on the expression of antimicrobial and anti-inflammatory genes in normal human epidermal keratinocytes (NHEKs). The suggested efficacy of PE in targeting pathogenic C. acnes biofilm, via downregulation of virulence genes, represents an alternative strategy to modulate the behavior of skin microbiota in acne, paving the way for next-generation acne-targeting products.