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Apigenin (APG), a plant-derived flavonoid, has attracted attention as an anti-melanoma agent because of its action on multiple cell signaling pathways and high selectivity for tumor cells. Despite this, extensive metabolism and slow oral absorption are found, which has motivated the development of topical delivery systems. In this context, invasomes were considered, for the first time, for flavonoid incorporation. Given that these vesicles have a more deformable structure than conventional liposomes, greater interaction with the skin is expected. In fact, ATR-FTIR analyses revealed more substantial changes in skin lipid domains with invasomes, which also were more stable to centrifugation and showed lower PDI values. Their reduced particle size (<200 nm), in turn, would allow reaching deeper tumor regions. The APG seems to interact with both polar and apolar domains of invasome lipids, which explains the high encapsulation efficiency (>99 %) and improved vesicle rigidity. Limonene, the terpene selected based on its already described anti-melanoma activity, was crucial for enhancing the retention of APG in the skin (an increase of more than 3.5x when compared to conventional liposomes) as well as vesicle stability. Cholesterol (CHOL) also slightly improved the permeation and retention of this flavonoid in the skin; however, it had a negative effect on the stability of APG-free invasomes. Taking into account the improved distribution of APG in the basal layer of the epidermis (the tumor site) and the advantages in terms of stability and membrane flexibility, invasomes can be considered promising colloidal carriers for the topical delivery of anti-melanoma drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)