© 2021 Elsevier B.V.The biophysical interaction between the nanoparticles (NPs) and biological interfaces is vitally important due to the increasing usage of NPs in biomedical and pharmaceutical applications such as drug delivery. Several different approaches or ligands can be utilized including surfactants for the surface decoration of NPs. We used two custom-made, positively charged and double-tailed surfactants which were hydrocarbon-based HHL (Hydrocarbon-Hydrocarbon Lipid) and fluorocarbon-hydrocarbon-based hybrid FHL (Fluorocarbon-Hydrocarbon Lipid) molecules to decorate the surface of negatively charged citrate-capped gold NPs (cit-AuNPs). Two model membranes were used throughout the study that were 1,2-dipalmitoyl-sn-glycero-3-phosphocoline (DPPC) and Endothelium model membrane (EMM). It was determined that although FHL and HHL have similar hydrophobicity, the lipophobicity of the fluorocarbon chain in the structure of FHL facilitates the interaction of AuNPs with model membranes and promotes the uptake of the particles. For EMM, it was observed that, the introduction of FHL-AuNPs provided 28 mN/m increase on π whereas HHL-AuNPs and CTAB-AuNPs gave rise to 12 mN/m and 7 mN/m, respectively, at constant area. In spite of the results obtained from DPPC and EMM monolayers were in similar trend, it is observed that the interaction of NPs with the membranes does not exhibit identical patterns signifying the need of using natural composition of lipids. As a result, hereby the vital parameters about the surface chemistry that influence the cellular uptake and the effect of AuNPs on the natural behavior of cell membranes were systematically examined which could be quite informative in designing a versatile and efficient nanocarrier system for drug delivery applications.