Abstract
The renal elimination pathway is increasingly harnessed to reduce nonspecific accumulation of engineered nanoparticles within the body and expedite their clinical applications. While the size of nanoparticles is recognized as crucial for their passive filtration through the glomerulus due to its limited pore size, the influence of nanoparticle charge on their transport and interactions within the kidneys remains largely elusive. Herein, we report that the proximal tubule and peritubular capillary, rather than the glomerulus, serve as primary charge barriers to the transport of charged nanoparticles within the kidney. Employing a series of ultrasmall, renal-clearable gold nanoparticles (AuNPs) with precisely engineered surface charge characteristics as multimodal imaging agents, we have tracked their distribution and retention across various kidney components following intravenous administration. Our results reveal that retention in the proximal tubules is governed not by the nanoparticle's zeta-potential, but by direct Coulombic interactions between the positively charged surface ligands of the AuNPs and the negatively charged microvilli of proximal tubules. However, further enhancing these interactions leads to increased binding of the positively charged AuNPs to the peritubular capillaries during the initial phase of elimination, subsequently facilitating their slow passage through the glomeruli and interaction with tubular components in a charge-selective manner. By identifying these two critical charge-dependent barriers in the renal transport of nanoparticles, our findings offer a fundamental insight for the design of renal nanomedicines tailored for selective targeting within the kidney, laying down a foundation for developing targeting renal nanomedicines for future kidney disease management in the clinics.