Hollow Polydopamine-Based Renal Tubule-Targeted Nanoplatform for Ferroptosis Inhibition and Fibrosis Amelioration

Background: Renal interstitial fibrosis (RIF) is a common pathological feature of chronic kidney disease progression to end-stage renal disease , currently lacks effective treatment options. Previous researches have indicated that ferroptosis plays a crucial role in driving renal RIF, and can be inhibited by ferroptosis inhibitors, such as rosiglitazone (Rosi). However, the clinical application of Rosi is hindered by poor water solubility, low renal accumulation, and systemic adverse effects. Methods: In this study, we constructed a renal tubular epithelial cell-targeted nano-based drug delivery system, Rosi@HPDA-PEG-K3 NPs. The hollow polydopamine (HPDA) nanoparticles loaded with Rosi were synthesized via a soft-template method, where the metal-chelating capacity of HPDA combined with the targeting modification by PEG-K3 synergistically enhanced drug delivery efficiency. Physicochemical characterizations including size, zeta potential, pH-responsive release were evaluated. Targeting experiment was conducted in vivo and tested by Cy5.5-based live imaging. The biosafety and antifibrotic efficacy of this system were also estimated in both TGF-β1-stimulated HK-2 cells and a unilateral ureteral obstruction mouse model. Results: Rosi@HPDA-PEG-K3 NPs exhibited superior stability and lesion-specific targeting, achieving prolonged retention in fibrotic kidneys. The pH-responsive release profile facilitated enhanced drug delivery at inflammatory sites while minimizing off-target exposure. In vitro and in vivo models demonstrated that this nano-based drug delivery system inhibited ferroptosis through downregulation of ACSL4, iron ion chelation, and ROS scavenging. Concurrently, it stabilized mitochondrial membrane potential and synergistically suppressed inflammatory responses, ultimately attenuating renal interstitial fibrosis. Conclusion: By integrating targeted Rosi delivery with multimodal mechanisms—ferroptosis inhibition, mitochondrial protection, and inflammation modulation—Rosi@HPDA-PEG-K3 NPs significantly ameliorated RIF progression with favorable biosafety. Our study advances mechanistic insights into ferroptosis regulation in renal fibrosis and establishes a nanotherapeutic platform with precise targeting, controlled release, and multifunctional efficacy, highlighting its scientific rigor and clinical translational potential. Funding: Government Support – Non-U.S.