Comparing the translocation of the bare and surface-functionalised gold nanoparticle across normal and...

Targeted drug delivery using nanoparticles holds significant promise for cancer therapy; however, the molecular mechanisms governing their interactions with normal membrane models and model membranes with cancer-associated lipid features remain insufficiently understood. Here, we employed atomistic molecular dynamics simulations combined with the adaptive biasing force (ABF) method to investigate the membrane interaction and translocation behaviour of bare gold nanoparticles (AuNPs), methane thiol-functionalised AuNPs, and octane thiol-functionalised AuNPs across molecular models of normal membranes and membranes with cancer-associated lipid features. Methane thiol and octane thiol coatings were selected to examine how increasing ligand-chain length and hydrophobicity influence nanoparticle-membrane interactions and free-energy profiles. The cholesterol-rich normal membrane exhibited higher structural order and increased resistance to nanoparticle permeation, whereas the cancer-mimicking membrane model displayed increased disorder and enhanced fluidity. Free-energy profiles revealed substantial energetic barriers to AuNP permeation in the normal membrane, while the cancer-mimicking membrane model showed enhanced membrane accommodation of bare AuNPs, although complete translocation remained energetically demanding. Bare AuNP translocation was associated with transient pore-like hydrated defects and water co-transport, whereas thiol functionalisation reduced local solvent penetration into the membrane core. Surface functionalisation modulated the free-energy landscape, indicating that ligand chemistry plays a critical role in tuning membrane insertion, partitioning, and retention. In particular, octane thiol-functionalised AuNPs exhibited strong hydrophobic membrane partitioning, but the resulting deep PMF minima indicate possible bilayer retention rather than efficient complete translocation. These findings provide mechanistic insight into nanoparticle-membrane interactions and provide molecular-level insight into how ligand hydrophobicity and membrane composition influence AuNP-membrane interactions in simplified model membrane systems.