TransfersomILs: A Synergy to Boost the Skin Delivery of Hydroxycinnamic Acids

Background/Objectives: Innovative topical delivery systems are needed to improve the stability, loading capacity, and performance of poorly water-soluble bioactive compounds. TransfersomILs, hybrid nanosystems combining transfersomes with ionic liquids (ILs), represent a promising strategy for this purpose. This work assessed the effect of incorporating cholinium-based ILs into transfersomal formulations loaded with hydroxycinnamic acids (HCAs)-ferulic, caffeic, and p-coumaric acids. Methods: TransfersomILs were prepared by the thin-film hydration method followed by sonication, with or without HCA incorporation. Formulations were characterised in terms of physicochemical properties, storage stability and impact on keratinocyte viability. In vitro release, permeation, and occlusion studies were also performed. Results: IL incorporation significantly improved formulation performance. TransfersomILs showed smaller vesicle sizes and more negative zeta potential values than conventional transfersomes, indicating improved physicochemical characteristics. ILs also increased association efficiency and loading capacity for all HCAs, although the magnitude depended on both the IL and the compound. Release profiles were compound-dependent, reflecting distinct release kinetics due to variable HCA-IL-membrane interactions. Permeation studies showed enhanced HCA flux across both silastic and human epidermal membranes compared with aqueous solutions and/or conventional transfersomes, with [Cho][Gly] generally showing superior performance. All formulations demonstrated acceptable cytocompatibility and occlusive properties. Conclusions: The combination of transfersomes and cholinium-based ILs demonstrated a synergistic effect, highlighting transfersomILs as a versatile platform for improving the topical delivery of HCAs.