Understanding of drug-carrier interactions is essential for the design and application of metal-organic framework (MOF)-based drug-delivery systems,a nd such drug-carrier interactions can be fundamentally different for MOFs with or without defects.Herein, we reveal that the defects in MOFs play ak ey role in the loading of many pharmaceuticals with phosphate or phosphonate groups.T he host-guest interaction is dominated by the Coulombic attraction between phosphate/ phosphonate groups and defect sites,a nd it strongly enhances the loading capacity.F or similar molecules without ap hosphate/phosphonate group or for MOFs without defects,t he loading capacity is greatly reduced. We employed solid-state NMR spectroscopyand molecular simulations to elucidate the drug-carrier interaction mechanisms.T hrough as ynergistic combination of experimental and theoretical analyses,t he docking conformations of pharmaceuticals at the defects were revealed.