Single-particle adsorption of ultra-small gold nanoparticles at the biomembrane phase boundary

Nanomaterials are revolutionizing biomedical research by enabling the development of novel therapies, with applications ranging from drug delivery and diagnostics to the modulation of specific biological processes. Current research focuses on tasks such as enhancing cellular uptake of materials while preserving their functionality. However, the mechanisms governing interactions between nanomaterials and biological systems-particularly cellular membranes-remain challenging to elucidate due to the complex, dynamic nature of the lipid bilayer environment. This complexity arises from factors such as coexisting lipid domains (conserved regions of lipids) or lipid rafts, as well as cellular behaviors that induce state changes. The heterogeneous membrane landscape may offer unique adsorption properties and other functional effects, making it crucial to understand these interactions for greater biological control in nanotherapeutics. In this work, we systematically expose a phase-separated phospholipid-supported lipid bilayer (SLB)-specifically, a fluid-gel DOPC:DPPC bilayer-to low concentrations of citrate-capped 5 nm gold nanoparticles (AuNPs) to observe the adsorption process of individual AuNPs at the molecular scale. Using atomic force microscopy (AFM), we experimentally detect the adsorption of some AuNPs at the phase boundary. Complementary molecular dynamics (MD) simulations further elucidate the mechanism of single AuNP adsorption at lipid phase boundaries. Our findings indicate that the AuNP preferentially incorporates into the fluid-phase DOPC lipids while maintaining partial association with the gel-phase DPPC lipids due to diffusion effects. During adsorption, the AuNP disrupts lipid organization by increasing lateral lipid mixing across the phase boundary. This disruption to lipid molecular ordering is further evident upon AuNP incorporation into the bilayer. The ability to modulate the spatial organization and structure of lipid molecules has significant implications for therapeutics that leverage lipid diffusion pathways for alternative drug delivery mechanisms or to induce specific lipid behaviors.