Lysozyme-Associated Quercetin–Manganese Nanocomposites for Kidney-Targeted Antiferroptotic Therapy of Acute Kidney Injury

Abstract Acute kidney injury (AKI) is a life-threatening syndrome in which oxidative stress, ferroptosis, and inflammatory amplification converge to damage renal proximal tubular epithelial cells. Although antioxidant and antiferroptotic therapies are conceptually attractive, their efficacy is restricted by rapid clearance and insufficient accumulation in injured renal tubules. Here, we report lysozyme-associated quercetin–manganese metal–phenolic nanocomposites (QMLNCs) as a kidney-targeted therapeutic platform for AKI. In this design, quercetin (QCT) functions simultaneously as an antioxidant drug and a phenolic coordination ligand, while Mn2+ participates in metal–phenolic network formation. Lysozyme is incorporated through noncovalent protein–polyphenol interactions to enhance megalin-mediated uptake by proximal tubular cells. QMLNCs exhibited favorable colloidal stability, H2O2-responsive release, and broad-spectrum radical-scavenging ability. In cisplatin-injured human kidney 2 (HK-2) cells, QMLNCs reduced Fe2+ and reactive oxygen species (ROS) accumulation, preserved mitochondrial membrane potential. Mechanistically, Western blot analysis indicated that QMLNCs could restore the protein levels of SLC7A11, GPX4, and FTH-1, which are key mediators of ferroptosis resistance. In macrophages, QMLNCs suppressed M1 polarization, promoted M2 polarization, and reduced tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) production. In vivo, QMLNCs preferentially accumulated in injured kidneys and significantly alleviated renal dysfunction in both glycerol-induced and cisplatin-induced AKI models, as indicated by decreased serum creatinine, blood urea nitrogen, MDA and pro-inflammatory cytokines. Overall, QMLNCs integrate renal tubular targeting, ROS scavenging, ferroptosis inhibition, and inflammation modulation into a single metal-natural product nanoplatform, offering a promising strategy for multimodal AKI therapy.