Abstract

Transethosomes are advanced lipid-based nanocarriers engineered to improve the transdermal delivery of therapeutic agents by combining phospholipids, ethanol, and edge activators (EAs), resulting in enhanced membrane fluidity, deformability, and skin penetration. This study aims to develop and optimize a novel transethosome-based delivery system for retinyl acetate (RA) to overcome its inherent limitations—including poor stability, low bioavailability, and skin irritation—thereby enhancing its therapeutic potential for dermatological and cosmetic applications. The transethosomes were prepared using phosphatidylcholine (PC) from soybean lecithin (SoyPC)/cholesterol (Chol) and 1,2-dioleoyl-sn-glycero-3-phosphocholine/1,2-dipalmitoyl-sn-glycero-3-phosphocholine/Chol (DOPC/DPPC/Chol), with various EAs including Tween-20, Tween-80, oleic acid (OA), and palmitic acid (PA). Physicochemical characterization revealed vesicle sizes ranging from 168.2 to 246.6 nm, low polydispersity index (PDI ≈ 0.2), and zeta potentials (ζ potential) between − 28 to − 30 mV, indicating uniform distribution and colloidal stability. All formulations exhibited spherical morphology, negative surface charge, and comparable encapsulation efficiencies (close to 90%). In vitro antioxidant activity showed moderate free radical scavenging effects, with up to ~ 40% and ~ 30% in the DPPH and ABTS assay. All formulations showed biocompatibility and improved migration in HaCaT cell assays. Due to the greater membrane fluidity of the SoyPC/Chol system, RA release may be more hindered compared to the DOPC/DPPC/Chol system. Consequently, RA release from the DOPC/DPPC/Chol system was more pronounced, resulting in the greatest enhancement in wound healing and outperforming all other formulations containing different EAs. In contrast, among the SoyPC/Chol formulations, those containing OA and PA exhibited more pronounced and effective results compared to those with Tween-based EAs. This suggests that OA and PA disrupt membrane stability to a greater extent than Tween, thereby facilitating enhanced RA release in the SoyPC/Chol system. Skin permeation studies also revealed that the type of EAs significantly influenced transdermal delivery. Confocal laser scanning microscopy (CLSM) further validated the role of EAs in modulating membrane organization. Overall, RA-loaded transethosomes enhanced stability, bioavailability, and skin penetration while minimizing irritancy of RA, supporting their potential in dermatological applications. Future studies should investigate their clinical efficacy and biophysical mechanisms, including line tension analysis, to optimize formulation performance for anti-aging and therapeutic skincare.