The quest for the construction of multivalent carbohydrate systems, with precise geometries that are highly efficient in interacting with carbohydrate binding proteins, has been a goal of synthetic chemists since the discovery of the multivalent nature of carbohydrate-mediated interactions. However, the control of the spatial and topological requirements for these systems is still a challenge. Glyconanoparticles (GNPs) are sugar-coated gold, iron oxide or semiconductor nanoparticles with defined thiol-ending glycosides that combine the multivalent presentation of carbohydrates (glycoclusters) with the special chemico-physical properties of the nano-sized metallic core. The possibility of attaching different types of carbohydrates and other molecules (such as luminescent probes, peptides, and magnetic chelates) onto the same gold nanoparticle in a controlled way (multifunctional GNPs), as well as modifying the core in order to obtain glyconanoparticles with magnetic or fluorescence properties (multimodal GNPs) makes this multivalent glyco-scaffold suitable for carrying out studies on carbohydrate-mediated interactions and applications in molecular imaging. In this review, we focus mainly on the rational design of glyconanoparticles as scaffolds for combining different ligands and survey the most recent examples of glyconanoparticles as both multivalent carbohydrate systems and probes for molecular imaging.

The primary function of the cell membrane is to protect cells from their surroundings. This entails a strict regulation on controlling the exchange of matter between the cell and its environment. A key factor when considering potential biological applications of a particular chemical structure has to do with its ability to internalize into cells. Molecules that can readily cross cell membranes are frequently needed in biological research and medicine, since most therapeutic entities are designed to modulate intracellular components. However, the design of molecules that do not penetrate cells is also relevant toward, for example, extracellular contrast agents, which are most widely used in clinical diagnosis. Small molecules have occupied the forefront of biomedical research until recently, but the past few decades have seen an increasing use of larger chemical structures, such as proteins or nanoparticles, leading to unprecedented and often unexpectedly novel research. Great achievements have been made toward understanding the rules that govern cellular uptake, which show that cell internalization of molecules is largely affected by their size. For example, macromolecules such as proteins and nucleic acids are usually unable to internalize cells. Intriguingly, in the case of nanoparticles, larger sizes seem to facilitate internalization via endocytic pathways, through which the particles remain trapped in lysosomes and endosomes. In this Account, we aimed at presenting our personal view of how different chemical structures behave in terms of cell internalization due to their size, ranging from small drugs to large nanoparticles. We first introduce the properties of cell membranes and the main mechanisms involved in cellular uptake. We then discuss the cellular internalization of molecules, distinguishing between those with molecular weights below 1 kDa and biological macromolecules such as proteins and nucleic acids. In the last section, we review the biological behavior of nanoparticles, with a special emphasis on plasmonic nanoparticles, which feature a high potential in the biomedical field. For each group of chemical structures, we discuss the parameters affecting their cellular internalization but also strategies that can be applied to achieve the desired intracellular delivery. Particular attention is paid to approaches that allow conditional regulation of the cell internalization process using external triggers, such as activable cell penetrating peptides, due to the impact that these systems may have in drug delivery and sensing applications. The Account ends with a "Conclusions and Outlook" section, where general lessons and future directions toward further advancements are briefly presented.

Poly(ethylene glycol) (PEG) has become the gold standard for stabilization of plasmonic nanoparticles (NPs) in biofluids, because it prevents aggregation while minimizing unspecific interactions with proteins. Application of Au NPs in biological environments requires the use of ligands that can target selected receptors, even in the presence of protein-rich media. We demonstrate here the stabilizing effect of low-molecular-weight glycans on both spherical and rod-like plasmonic NPs under physiological conditions, as bench-marked against the well-established PEG ligands. Glycan-coated NPs are resistant to adsorption of proteins from serum-containing media and avoid phagocytosis by macrophage-like cells, but retain selectivity toward carbohydrate-binding proteins in protein-rich biological media. These results open the way toward the design of efficient therapeutic/diagnostic glycan-decorated plasmonic nanotools for specific biological applications.