Impact of α-tocopherol derivatives on the structural and functional properties of model lipid nanocarriers: A biophysical modeling study

While α-tocopherol is widely studied for its antioxidant role in membranes, its potential as a functional component of liposomal carriers remains underexplored, despite their range of interesting biological activities and growing use in nanocarrier systems. This study systematically evaluates how three tocopherol derivatives - α-tocopherol phosphate (TP), α-tocopherol succinate (TS), and α-tocopherol polyethylene glycol succinate (TPGS)—affect nanoliposomes, focusing on colloidal stability, encapsulation efficiency, and fundamental membrane properties such as fluidity, hydration, and thermotropic behavior. Results showed that all α-tocopherol derivatives significantly altered membrane properties, inducing structural changes in both the lipid chain and polar regions of the liposome bilayer. TS enhanced membrane rigidity and reduced permeability, while TP increased fluidity and promoted payload release. TPGS, with its bulky PEG chain, stabilized liposomes but induced phase heterogeneity. Additionally, all derivatives lowered the lipid main phase transition temperature and altered its thermotropic behavior. Despite these disruptions, the derivatives preserved nanoscale vesicle sizes (~100 nm) and monodisperse distributions (PDI < 0.3) over extended storage. These experimental observations were further supported by molecular dynamics simulations, which confirmed differences in membrane affinity among the derivatives, with TS showing the strongest binding affinity. The simulations also revealed that the derivatives' positioning within the bilayer and their interactions—mainly hydrogen bonding and hydrophobic contacts—contribute to their distinct effects on membrane structure and dynamics. Collectively, these findings demonstrate that α-tocopherol derivatives distinctly modulate liposomal membrane architecture and behavior in a structure-dependent manner, offering promising tools for tuning nanocarrier performance in pharmaceutical applications. • This study explores the potential of α-tocopherol derivatives as valuable tools for designing stable and adaptable liposomal carriers, taking advantage of their unique biological properties and strong interaction with lipid membranes to improve drug delivery. • All three tocopherol derivatives (TP, TS, TPGS) significantly altered membrane fluidity and phase transition behavior affecting in structural changes in both hydrophobic and hydrophilic parts of liposomal bilayer. • Molecular dynamics simulations establish α-tocopherol succinate (TS) as the strongest membrane anchor, combining optimal hydrophobic and electrostatic which is a complementary to the experimental results. • All α-tocopherol derivatives preserved critical pharmaceutical parameters - maintaining nanoscale vesicle sizes (~100 nm), monodisperse distributions (PDI < 0.25) and high colloidal stability (~ -30 mV) throughout 30-day storage.