Type IV Collagen-Targeting Nanoparticles for Efficient Delivery to the Renal Interstitium in Fibrotic Kidneys

Renal fibrosis is recognized as the final common pathway of chronic kidney disease (CKD) progression, ultimately leading to end-stage renal failure and defined by excessive accumulation of extracellular matrix (ECM) by renal myofibroblasts in the interstitium. To establish an effective drug delivery system targeting fibrotic lesions, we developed nanoparticles modified with short-chain peptides that bind type IV collagen (Col IV), a distinct ECM component remodeled in fibrosis.

Col IV-targeting nanoparticles were intravenously administered to a unilateral ureteral obstruction (UUO) rat model of renal fibrosis. The distribution of these nanoparticles to the renal interstitium was examined via fluorescence-based ex vivo imaging and analysis of frozen kidney tissue sections. Additionally, we assessed cellular uptake in renal fibroblasts (NRK-49F), with or without transforming growth factor-beta 1 (TGF-β1) stimulation, using flow cytometry.

Both Col IV-targeting and non-targeting nanoparticles exhibited increased distribution in the fibrotic renal interstitium compared to healthy tissue. Moreover, the Col IV-targeting nanoparticles localized more extensively in the fibrotic interstitium than their non-targeting counterparts. In vitro, Col IV-targeting nanoparticles also showed significantly higher accumulation in NRK-49F cells, irrespective of TGF-β1 stimulation, compared to non-targeting nanoparticles.

In a UUO-induced renal fibrosis model, these nanoparticles efficiently migrated to the fibrotic renal interstitium, and in vitro experiments using NRK-49F cells demonstrated enhanced uptake by renal fibroblasts and myofibroblasts, central mediators of ECM deposition in fibrotic progression.

We successfully fabricated and evaluated Col IV-targeting nanoparticles, which may serve as an effective drug delivery platform for antifibrotic therapies, potentially mitigating CKD progression.