Renal-Clearable Gold Nanoparticles Serve as Blood Markers for Detection of Proximal Tubular Injuries

Engineered nanoparticles designed for renal clearance can minimize nonspecific accumulation and toxicity, with particles under 5–8 nm efficiently filtered through the glomeruli. While glomerular injury disrupts these barriers and causes proteinuria, its effect on nanoparticle clearance remains unclear. After filtration, nanoparticle retention in proximal tubules depends on surface charge and epithelial interactions, but tubular injury reduces uptake, promotes obstruction, and prolongs retention. Although kidney injury molecule-1 (KIM-1) is a sensitive urinary biomarker of proximal tubular damage, its relationship to nanoparticle transport and clearance has not been systematically investigated.

Au₂₅(SG)₁₈, a glutathione-coated gold nanocluster with efficient renal clearance (~50% excreted in urine within 2 h) and distinct optical/NIR signatures, was used as a multimodal probe for kidney studies. A doxorubicin-induced kidney injury model (20 mg kg⁻¹, i.v.) was established in BALB/c mice, which consistently produced proteinuria and both glomerular and tubular damage; 8–10 mice per group ensured sufficient statistical power. Four days post-treatment, mice received Au₂₅(SG)₁₈ (100 mg kg⁻¹, weight-adjusted), and blood, urine, and kidneys were collected 30 min later for ICP-MS quantification and biomarker analysis (proteinuria, KIM-1/creatinine, BUN, sCr, creatinine clearance). Long-term studies confirmed efficient clearance, with <1.5% of Au₂₅(SG)₁₈ retained in any organ one month after injection.

DOX-induced glomerular injury led to >50-fold proteinuria, yet Au₂₅(SG)₁₈ exhibited 1.8-fold higher blood retention, reflecting reduced GFR rather than enhanced clearance. Proteinuria correlated strongly with impaired nanoparticle excretion (r = −0.83) and increased kidney accumulation, highlighting distinct elimination pathways for proteins and nanoparticles. Severe proximal tubular injury was also observed, with a ~4.4-fold rise in urinary KIM-1, cortical necrosis, brush border loss, and tubular obstruction by casts and sloughed cells. Consequently, kidney accumulation of Au₂₅(SG)₁₈ increased more than threefold, while renal clearance dropped from 58.7% to 16.6% of the injected dose. Importantly, blood clearance of Au₂₅(SG)₁₈ correlated most strongly with urinary KIM-1 (r = 0.90), exceeding correlations with traditional GFR markers or urinary excretion. These results suggest that renal-clearable nanoparticles such as Au₂₅(SG)₁₈ can serve as sensitive blood-based indicators of proximal tubular injury, offering clear advantages over conventional biomarkers.

Kidney elimination is a major pathway for engineered nanoparticle clearance, making it critical to understand how kidney disease alters their in vivo transport. Using a DOX-induced kidney injury model, we found that increased glomerular permeability did not accelerate Au₂₅(SG)₁₈ clearance; instead, reduced glomerular filtration caused by tubular injury was the primary determinant of its blood retention and renal clearance. Among renal biomarkers, blood clearance of Au₂₅(SG)₁₈ correlated most strongly with urinary KIM-1 (r = 0.90), outperforming conventional GFR markers such as BUN, serum creatinine, and creatinine clearance (r < 0.8). Similar results were observed in cisplatin-induced tubular injury without glomerular damage, confirming that tubular injury governs nanoparticle clearance. These findings highlight renal-clearable Au₂₅(SG)₁₈ as a sensitive blood-based marker for tubular injury, complementing its potential as a urinary marker and contrast agent for kidney disease diagnosis.