Nonspecific Interactions of Amphiphilic Nanoparticles and Biomimetic Membranes

Robust control over nanoparticle (NP)-cell interactions is essential to the rational design of safe, advanced, and tailored nano-bio technologies. Achieving control over NP behavior at the cellular interface relies on the fundamental need to elucidate the physicochemical principles underlying the interactions between NPs and cell membranes. Despite numerous research efforts, the propensity of surface-modified NPs to interfere (or not) with the organization and function of cell membranes is still far from clear due to the inherently complex and dynamic nature of these biological barriers. In this thesis, experimental investigations were undertaken to tackle some aspects of nonspecific NP-membrane interactions that are still unclear or very poorly addressed. Sub-5 nm gold NPs protected by a mixture of hydrophobic and ω-charged hydrophilic thiols were considered. These amphiphilic NPs possess high biomedical potential as they are able to passively enter living cells for theranostic purposes. Based on a biomimetic approach, lipid bilayers of varying structural and morphological complexity were employed to model the lipid structure of cell membranes. This work revealed that the sign of the NP surface charge is not responsible for different NP behavior in the interaction with neutral membranes. Notably, anionic and cationic NPs were shown not to damage the membrane integrity during passive bilayer penetration. Furthermore, anionic NPs were revealed to perturb the lateral lipid phase separation of multidomain membranes in a concentration-dependent manner and form peculiar bilayer-embedded ordered aggregates. Finally, the cholesterol-tuned reduction in bilayer fluidity was disclosed to dramatically hinder passive NP uptake into fluid membranes. Taken together, these findings provide a novel contribution in elucidating how amphiphilic entities endowed with surface conformational flexibility, such as ligand-protected NPs, can interact with cell membranes.