Multifunctional Polydopamine Nanoparticles to Alleviate Oxidative Stress and Inhibit Ferroptosis for Cisplatin-Induced Acute Kidney Injury Therapy.

Abstract

Acute kidney injury (AKI) is a clinical syndrome with high incidence and mortality involving oxidative stress, ferroptosis, and inflammation, yet there are no clinically effective interventions. Herein, HA@PDA@EGCG nanoparticles were constructed using polydopamine (PDA) as carriers, loaded with epigallocatechin gallate (EGCG) via π-π stacking, and further surface-modified with hyaluronic acid (HA) through electrostatic interaction. The nanoparticles had uniform morphology with a size of approximately 50 nm and an EGCG loading capacity of 15.4 ± 0.8%. They exhibited prominent broad-spectrum antioxidant activity and hydrogen peroxide-responsive EGCG release, with a cumulative release rate of 58.2 ± 2.2% within 2 h and close to 80% at 12 h. Cellular uptake and in vivo distribution confirmed the efficient CD44 receptor-mediated internalization of the nanoparticles by human kidney-2 (HK-2) cells as well as renal-targeted accumulation. Reactive oxygen species (ROS) staining, mitochondrial morphology and apoptosis assays showed that the nanoparticles effectively scavenged ROS, alleviated mitochondrial damage, and inhibited cell apoptosis. In a cisplatin-induced in vivo AKI model, HA@PDA@EGCG significantly restored renal function: blood urea nitrogen and creatinine decreased to 12.3% and 27.2% of model group levels, respectively, while alleviating renal pathological damage and inflammation. Mechanistically, HA@PDA@EGCG inhibited ferroptosis by downregulating acyl-CoA synthetase long-chain family member 4 (ACSL4) to suppress lipid synthesis, chelating ferrous ions, and stabilizing glutathione peroxidase 4 (GPX4) protein. Collectively, HA@PDA@EGCG achieved renal protection by ameliorating oxidative stress, suppressing inflammation and inhibiting ferroptosis through multiple pathways, offering a novel strategy for targeted AKI therapy.