**Background:** Diabetic retinopathy (DR) is a leading cause of blindness in adults, driven by hyperglycemia-induced oxidative stress pathways including POLDIP2, which activates NOX4 to produce excess ROS, upregulating VCAM-1, HIF-1α, and VEGF and causing microvascular dysfunction. Dihydromyricetin (DMY) is a natural flavonoid antioxidant with poor solubility, short half-life (t1/2 = 3.70 ± 0.99 h), and low oral bioavailability (4.02%). The authors aimed to synthesize Fe-DMY nanoscale coordination polymers (NCPs) to improve DMY delivery and evaluate their efficacy against DR.
**Methods:** Fe-DMY NCPs were synthesized by coordinating DMY with FeCl3·6H2O in the presence of polyvinylpyrrolidone (PVP) in methanol, followed by dialysis and ultracentrifugation. Characterization included TEM, zeta potential, FTIR, and XPS. In vitro radical scavenging was assessed using ABTS, DPPH, MB (·OH), and PTIO assays. HUVEC were cultured in normal (7 mM) or high glucose (30 mM) medium for 48 h to model DR. Cell viability was measured by CCK-8 assay; intracellular ROS by DCFH-DA staining (confocal microscopy, flow cytometry, plate reader). Tube formation was assessed on Matrigel. Protein expression (Poldip2, Nox4, VCAM-1, HIF-1α, VEGF) was quantified by Western blot and ELISA. In vivo, 8-week-old male SD rats were injected with streptozotocin (STZ) to induce diabetes (blood glucose ≥20 mmol/L). DR rats received oral Fe-DMY NCPs (60 or 10 mg/kg) or saline every three days for 14 weeks. Retinal and plasma DMY concentrations were measured by HPLC on days 3, 7, and 14. Retinal histology (HE staining), vascular leakage (Evans blue), ROS (dihydroethidium staining), H2O2 levels (serum and retina), and protein expression (WB, ELISA) were evaluated. Biosafety was assessed by HE staining of major organs.
**Key Results:** Fe-DMY NCPs were ultra-small (<10 nm), negatively charged (−18.37 ± 0.75 mV), and showed enhanced water solubility. They scavenged >90% of ·OH radicals at >100 μg/mL, >90% of ABTS radicals at 40 μg/mL, >90% of DPPH radicals at >100 μg/mL, and >90% of PTIO radicals at >200 μg/mL. In HUVEC, Fe-DMY NCPs increased cell viability in a dose- and time-dependent manner (ED50 = 35.39 μg/mL). High glucose (30 mM) increased intracellular ROS (DCF fluorescence) and upregulated Poldip2, Nox4, VCAM-1, HIF-1α, and VEGF; Fe-DMY NCPs (200 μg/mL) significantly reduced ROS and all five proteins (P < 0.0001 vs. DC). Tube formation assays showed that Fe-DMY NCPs dose-dependently inhibited neovascularization (vessel area, density, branching, length; P < 0.0001). In DR rats, oral Fe-DMY NCPs maintained retinal DMY concentrations >20 μg/mL and plasma DMY >50 μg/mL over 14 days. High-dose (60 mg/kg) Fe-DMY NCPs reduced blood glucose, improved body weight, and alleviated polydipsia/polyphagia. HE staining showed that DR rats had thinned ONL and INL, edematous ganglion cell layer, and cataract; high-dose Fe-DMY NCPs restored retinal structure and reduced cataract severity. Evans blue staining revealed reduced vascular leakage and neovascularization in treated rats. Retinal ROS fluorescence intensity and H2O2 levels (both serum and retina) were significantly elevated in DC and reduced by Fe-DMY NCPs (P < 0.0001). WB and ELISA confirmed that Fe-DMY NCPs downregulated Poldip2, Nox4, VCAM-1, HIF-1α, and VEGF in retinal tissue (P < 0.0001). HE staining of heart, liver, spleen, lung, kidney, and brain showed no pathological changes.
**Clinical Implications:** Fe-DMY NCPs represent a novel, orally bioavailable nanotherapeutic that targets the Poldip2-Nox4-H2O2 oxidative stress pathway, a key driver of DR pathology. By scavenging ROS and downregulating VCAM-1, HIF-1α, and VEGF, Fe-DMY NCPs reduce retinal vascular leakage and neovascularization, addressing both early and proliferative stages of DR. The excellent biosafety profile (no organ toxicity at tested doses) and improved pharmacokinetics over free DMY suggest potential for clinical translation as a safe, effective antioxidant and microangio-protective agent for DR and possibly other oxidative stress-related diseases. Further long-term studies are needed to assess chronic iron accumulation and ferroptosis-related effects.