Nanoparticle Transport in Proximal Tubules with Rhabdomyolysis‐Induced Necrosis

Abstract Renal‐clearable engineered nanoparticles are being explored for their potential to deliver therapeutic agents for kidney disease treatment. A fundamental understanding of how these nanoparticles accumulate in diseased kidneys at the cellular level is essential to enhance their effectiveness and minimize side effects on adjacent healthy tissues. Herein, we report that the accumulation of glutathione‐coated, near‐infrared emitting gold nanoparticles (GS‐AuNPs) correlates strongly with the necrotic stages of injured proximal tubular cells. Using a rhabdomyolysis‐induced acute kidney injury (AKI) mouse model, we observed that GS‐AuNPs were significantly accumulated in the extracellular lumen of proximal tubular epithelial cells (PTECs) at advanced necrotic stage, where cellular debris and released intracellular contents impeded their clearance. In contrast, during early necrosis, GS‐AuNPs were still cleared through the unobstructed lumen. Additionally, intracellular uptake of GS‐AuNPs was significantly reduced across all necrotic stages. These findings underscore the need for new strategies to design nanoparticles that can effectively target and be taken up by the diseased tubular cells before extensive necrosis occurs; so that nanoparticle‐mediated drug delivery for kidney disease treatment can be achieved with desired efficacy and precision.