Abstract
Functionalized metal nanoparticles (NPs) hold great promise as innovative tools in nanomedicine. However, one of the main challenges is how to optimize their association with the cell membrane, which is critical for their effective delivery. Recent findings show high cellular uptake rates for NPs coated with the polycationic cell-penetrating peptide gH625-644 (gH), although the underlying internalization mechanism is poorly understood. Here, we use extended coarse-grained simulations and free energy calculations to study systems that simultaneously include metal NPs, peptides, lipids, and sterols. In particular, we investigate the first encounter between multicomponent model membranes and 2.5 nm metal NPs coated with gH (gHNPs), based on the evidence from scanning transmission electron microscopy. By comparing multiple membrane and (membranotropic) NP models, we found that gHNP internalization occurs by forming an intermediate state characterized by specific stabilizing interactions formed by peptide-coated nanoparticles with multicomponent model membranes. This association mechanism is mainly characterized by interactions of gH with the extracellular solvent and the polar membrane surface. At the same time, the NP core interacts with the transmembrane (cholesterol-rich) fatty phase.
Highlights
Functionalized metal nanoparticles (NPs) are gaining attention because they display tunable surface chemistry dictated by coating a monolayer of organic molecules.[1−5]These NPs hold promise in numerous biomedical applications from imaging[6] to cancer therapy,[7] most of which require the accumulation of NPs inside targeted cells.[8]
We built specific coarse-grained (CG) models for each of our studied systems, and we parametrized them with the Martini force field
Our four representative nanocarriers were: (i) a metal NP coated with six gH625-644 peptides, (ii) an individual gH peptide, (iii) a spherical, purely hydrophobic NP (NP0, Figure 1c), and (iv) a spherical citratecapped NP (CitNP, Figure 1d)
Summary
Functionalized metal nanoparticles (NPs) are gaining attention because they display tunable surface chemistry dictated by coating a monolayer of organic molecules (i.e., ligands).[1−5]. These NPs hold promise in numerous biomedical applications from imaging[6] to cancer therapy,[7] most of which require the accumulation of NPs inside targeted cells.[8] Functionalized NPs are typically internalized through energy-dependent pathways like receptor-mediated endocytosis, yet, in some rare cases, they can enter cells through passive diffusion or passive endocytosis.[9,10] Importantly, all of the above mechanisms are initiated by the nanomaterial’s association with cell membranes.[11,12] the exact association mechanism of a NP’s structure with biological barriers continues to be poorly understood. Other critical factors for modulating cell internalization include environmental variables such as culture media,[27−29] membrane curvature,[30] and, of relevance to this study, cholesterol abundance in the membrane.[31]
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