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

Abstract

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

Methods: 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.

Results: Both Col IV-targeting and non-targeting nanoparticles exhibited increased distribution in the fibrotic renal interstitium compared to healthy renal 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.

Conclusion: We successfully fabricated and evaluated Col IV-targeting nanoparticles as a potential drug delivery platform. 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. These findings suggest that Col IV-targeting nanoparticles may serve as an effective drug carrier for delivering antifibrotic therapies, potentially mitigating CKD progression.