HPDA-based tubule-targeting nanoplatform alleviates oxidative stress and ferroptosis for the reversal of renal interstitial fibrosis.

BACKGROUND: Renal interstitial fibrosis (RIF) is a hallmark pathological process in the progression of chronic kidney disease (CKD). However, effective therapies to halt or reverse RIF remain limited. Emerging evidence implicates ferroptosis as a critical contributor to RIF. Rosiglitazone (Rosi), a widely used thiazolidinedione, exhibits anti-ferroptotic activity but suffers from poor aqueous solubility, limited renal specificity, and systemic side effects. RESULTS: Here, we constructed a renal tubular epithelial cell-targeted nano-based drug delivery system-Rosi-loaded, K3 peptide-modified, PEGylated hollow polydopamine(HPDA) nanoparticles (Rosi@HPDA-PEG-K3 NPs). This system displayed excellent biocompatibility and lesion-specific targeting, achieving prolonged retention in fibrotic kidneys. The in vitro and in vivo experiment 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 RIF. CONCLUSIONS: In summary, Rosi@HPDA-PEG-K3 NPs deliver Rosi specifically to renal renal tubular epithelial cells(TECs)and exert an anti-RIF effect through the integration of ferroptosis inhibition, mitochondrial protection, and inflammation modulation. Our study establishes a nanotherapeutic platform with precise targeting and multifunctional efficacy, highlighting its scientific rigor and the clinical translational potential of RIF.