Transdermal Behavior and Molecular Dynamics Simulation of Chitosan-Cross-Linked Sapindus Extract Liposomes

To enhance the skin permeability and retention of Sapindus saponins, cationic liposomes are fabricated via a thin-film dispersion method followed by electrostatic cross-linking with chitosan. The Franz diffusion cell method is used to evaluate the transdermal performance, while molecular dynamics (MD) simulations (50 ns) are employed to elucidate the self-assembly mechanism and intermolecular interactions. The optimized preparation conditions are determined as Sapindus saponin extract concentration of 15 mg/mL, soybean lecithin dosage of 350 mg, lecithin: stigmasterol mass ratio of 4:1, and hydration temperature of 55 °C. Under these conditions, the liposomes achieve an encapsulation efficiency of 87.89 ± 2.85%. Upon modification with chitosan (volume ratio of 0.8), the ζ potential reverses to positive (+39.9 ± 1.7 mV). Transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC) confirm the formation of a core–shell structure and the amorphization of the encapsulated components. Notably, the cationic liposomes exhibit a 24 h cumulative permeation rate of 63.92% (2.08 times that of conventional liposomes) and, more importantly, a skin retention rate of 7.09% (5.0 times higher), demonstrating a significant local drug reservoir effect. MD simulation results reveal that the system self-assembles into vesicular complexes driven by van der Waals forces, hydrogen bond networks, and strong electrostatic anchoring. Specifically, robust electrostatic attractions form between the phosphate groups of lipids and the amino groups of chitosan, while a diffuse hydrogen bond network creates a rigid protective coating. These interactions serve as the core forces, maintaining the structural stability and preventing drug leakage.