Heparin-Binding Proteins in the Nanoparticle Corona: An Overlooked Player at the Bio–Nano Interface

When nanoparticles (NPs) enter biological environments, they rapidly acquire a layer of adsorbed proteins, known as the protein corona, which plays a central role in their interactions with cells. While extensive work has focused on how corona proteins interact with cell-surface receptors to modulate NP uptake, the role of corona–glycocalyx interactions has received comparatively little attention. In this Minireview, we highlight emerging evidence that heparin-binding proteins (HBPs) within the protein corona can engage glycosaminoglycans, such as heparan sulfate, in the cellular glycocalyx, thereby introducing an additional layer of molecular recognition at the cell surface. Drawing on recently published protein corona data sets, we further show that HBPs are frequently present and often abundant across protein coronas from diverse NP systems. These observations highlight HBPs as important, yet underappreciated, mediators of NP–cell interactions and uptake.