A Supramolecular Salicylic Acid-Betaine with Superior Epidermal Benefits and Better Tolerance: In vitro Proof of Concept Studies

INTRODUCTION: Recent progress in supramolecule research has led to a surge in its application in cosmetic products. However, comprehensive investigation of the potential benefits, especially differentiating biological activities and associating that with physical-chemical properties, remains to be established. The current study aimed to investigate the supramolecular salicylic acid-betaine (Supra-SA-B) compared to its physical mixture (SA+B) for effects on epidermal homeostasis and topical insult potential. METHODS: The structure of supra-SA-B and SA+B was characterized by a powder X-ray diffractometer. Skin tolerance was evaluated by applying SA, Supra-SA-B, and SA+B to human keratinocytes or SkinEthic™ reconstructed human epidermis (RHE) models. Inflammatory cytokines were assessed by Luminex assay. Histological morphology was evaluated by hematoxylin-eosin staining, with aquaporin-3 (AQP3) and Ki67 measured by immunofluorescence. RNA sequencing characterized overall biological response. RESULTS: Characteristic peaks remained the same for Supra-SA-B after freeze-drying verified that their crystalline structures were retained in the current solution. Supra-SA-B treated groups demonstrated significantly higher viabilities compared to SA or SA+B. With 18-h of treatment, Supra-SA-B treated group released fewer cytokines. In addition, Supra-SA-B demonstrated a better hydration effect with increased AQP3 expression and more organized epidermal structure. Consistent result was observed in the RNA transcriptomic profiles of RHE models. Supra-SA-B did not induce major transcriptome drift as compared to SA or SA+B, with less evident negative impact on loricrin, and late cornified envelope gene expression. Hyaluronic acid synthase boosting was maintained. CONCLUSION: Supra-SA-B ameliorated skin tolerance risk for SA, enhanced hydration with less insult on barrier functions, suggesting promising potential for cosmetic application.