Design and mechanistic insights of diacylglycerol-based microemulsions for enhanced transdermal delivery:...

A diacylglycerol (DAG)-based microemulsion system was designed and optimized for efficient transdermal delivery. Pseudo-ternary phase diagrams and D-optimal mixture design identified the optimal formulation (6.23 % DAG oil, 21.41 % RH-40, 18.09 % 1,3-propanediol, and 54.27 % water), yielding a transparent and stable microemulsion with a droplet size of 24.43 nm and infinite dilution capacity. The amphiphilic structure of DAG expanded the one-phase microemulsion region and reduced surfactant demand. Physicochemical evaluations confirmed excellent stability under centrifugation, thermal stress, and long-term storage. Molecular dynamics simulations showed that DAG molecules stabilized droplets at the oil-water interface, whereas triacylglycerol clusters destabilized and dispersed, underscoring the structural advantage of DAG. These nanoscale behaviors translated into superior delivery performance: in vitro studies confirmed that DAG-based microemulsions enhanced the drug transdermal permeation by 2.50-fold and increased dermal retention nearly 3.0-fold compared with oil solutions. Confocal imaging further demonstrated intact droplet penetration across skin layers. This work highlight the amphiphilic advantage of DAG in stabilizing microemulsions and facilitating dermal delivery of lipophilic bioactives, offering a promising route for safe, effective, and surfactant-efficient delivery platforms.