Physical interactions encompass electrostatic, hydrophobic, and affinity interactions. Physical conjugation strategies are particularly useful for the assembly of therapeutic agents onto nanoparticles. Electrostatic interactions are useful for loading siRNA onto nanoparticles coated with cationic PEI. Hydrophobic anticancer drugs can adsorbed via hydrophobic interactions onto nanoparticles coated with a hydrophobic coating layer, and the drugs may then be released inside cells after degradation of the coating layer. Although these interactions have several unique advantages, including rapid binding and the lack of modification steps, it is difficult to control the molecular orientations of physically bound ligands. This binding mode, therefore, is not appropriate for immobilizing targeting moieties. In contrast, affinity interactions are effective for bioconjugating targeting ligands to nanoparticles. A representative example of affinity interactions is the streptavidin-biotin interaction. This linkage is very stable and shows the strongest known binding affinity among non-covalent linkage reactions (Kd= 4.0 × 10-14 M) [].


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