Nonspecific Colloidal-Type Interaction Explains Size-Dependent Specific Binding of Membrane-Targeted Nanoparticles

Emerging biomedical applications such as molecular imaging and drug delivery often require directed binding of nanoparticles to cell-membrane receptors. The specific apparent affinity of such ligand-functionalized particles is size-dependent, an observation so far solely attributed to multivalent receptor–ligand interaction. We question the universality of this explanation by demonstrating that the binding kinetics also depends on weak, attractive colloidal-type interaction between nanoparticles and a lipid membrane. Applying label-free single-particle imaging, we correlate binding of nanoparticles targeted to a cell-mimetic lipid membrane with the distribution of nontargeted particles freely diffusing close to the membrane interface. This analysis shows that already a weak, k B T -scale attraction present between 50 nm gold nanoparticles and the membrane renders these particles an order of magnitude higher avidity compared to 20 nm particles. A stronger emphasis on nonspecific particle–membrane interaction might thus be required to accurately predict nanoparticle targeting and other similar processes such as cellular uptake of exosomes and viruses.