Lemon balm-derived nanovesicles restore mitochondrial function and reduce cytokine production in skin fibroblasts under pro-inflammatory conditions

Mitochondrial dysfunction, particularly excessive fission, has been implicated in inflammatory signalling in skin diseases such as psoriasis and atopic dermatitis (AD). Current systemic treatments, while effective, are often associated with adverse effects, variable patient responses and high costs. Plant extracts have shown notable anti-inflammatory properties; however, their therapeutic potential is limited due to low penetration and poor bioavailability. Thus, plant-derived nanovesicles (PDNVs) have emerged as an alternative delivery platform, offering bioactive cargo with improved skin penetration and low immunogenic potential. Melissa officinalis L. (Lemon Balm, LB) extracts have demonstrated beneficial effects in inflammatory skin conditions; however, the potential of LB-NVs to modulate skin cell function and cellular energetics in inflammatory conditions remains unexplored. Thus, this study investigated the effects of LB-NVs on mitochondrial function and structure in human skin fibroblasts exposed to a cytokine cocktail (IL-22, IL-17A, TNF-α) to induce a pro-inflammatory state (PInfS). LB-NVs rescued cells from inflammatory metabolic reprogramming by restoring mitochondrial respiration and preventing elevated glycolysis induced by PinfS. Additionally, they reduced mitochondrial fragmentation by regulating the activation of Drp1 and lowered the total p38 MAPK level. Lastly, LB-NVs suppressed IL-4 and IL-13, which are central to AD pathogenesis, and reduced IL-18, a cytokine that commonly increases with disease activity. These findings, for the first time, demonstrate the ability of PDNVs to directly target mitochondrial functions and modulate inflammation, positioning LB-NVs as a highly promising strategy for treating chronic skin inflammation.