Dendrimer 'protein corona': mechanism of interaction, characterization, and implications in drug delivery

Upon exposure to biological fluids, nanoparticles immediately interact with endogenous proteins and biomolecules, acquiring a 'protein corona' that significantly influences their in vivo behavior. Dendrimers are ultrasmall, highly branched nanocarriers whose physicochemical properties and cargo conjugation can be precisely tailored for drug delivery. Unlike larger nanoparticles, dendrimers are comparable in size to many plasma proteins, and their interactions in biological fluids give rise to 'dendrimer-protein complexes' that depart from the conventional coronal structure. These interactions redefine the biological identity of dendrimers and, in turn, modulate their pharmacological behavior. In this review, we first survey the broader roles of the protein corona in nanomedicine and then examine the functional consequences of dendrimer-protein interactions for cellular targeting, systemic clearance, and toxicity. We subsequently evaluate current models of dendrimer-protein binding kinetics and complex formation, emphasizing how dendrimer physicochemical properties govern these interactions and their downstream effects. Finally, we review the analytical and separation methods available for studying dendrimer-protein interactions and propose asymmetric flow field-flow fractionation (AF4) coupled with enrichment analysis as a promising strategy for resolving dendrimer-associated proteins. A mechanistic understanding of dendrimer-protein interactions will be essential for the rational design and clinical translation of dendrimer-based therapeutics.