Impact of Renal-Targeting Ligand Density on Kidney Targeting, Clearance, and Off-Target Effects of Renal-Clearable Nanoparticles

Renal-clearable nanoparticles hold great promise for kidney targeting and associated biomedical applications. Surface functionalization with renal-targeting ligands is an effective strategy for their kidney-specific targeting; however, it remains poorly understood how the ligand coating density affects their kidney-targeting efficiency, clearance, and off-target effects. Herein, utilizing a series of folate (FA)-conjugated ultrasmall gold nanoparticles with controlled FA densities to target renal folate receptors as a model system, we found that higher FA density enhanced kidney targeting in a Boltzmann sigmoidal function with an inflection at ∼3.20 FA/nm2, which was dictated by the association kinetics of nanoparticles with folate receptors. Meanwhile, increasing the FA density nonlinearly reduced renal clearance efficiency and elevated accumulation in extrarenal organs. By integrating these multiple effects, we identified a critical balance point of FA density at ∼5.28 FA/nm2 with enhanced renal targeting but without significantly compromising nonspecific biodistribution, providing critical guidance for the rational design of precision renal nanomedicine.