Fe₃O₄ coated stent prevent artery neointimal hyperplasia by inhibiting vascular smooth muscle cell proliferation

In-stent restenosis (ISR), caused by aggressive vascular smooth muscle cell (VSMC) proliferation, is a serious complication of stenting. Therefore, developing therapeutic approaches that target VSMC inhibition is imperative. Our previous study showed that VSMC hyperplasia was attenuated after iron stent degradation, and VSMC proliferation around the stented section was arrested. The corrosion products of the iron stents were primarily Fe₃O₄ particles. Therefore, we hypothesized that Fe₃O₄ particles generated by iron stents would prevent neointimal hyperplasia by inhibiting VSMC proliferation. To test this hypothesis, culture assays and flow cytometry were performed to investigate the proliferation of VSMC. Global gene sequencing and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to investigate the underlying mechanisms. Fe₃O₄-coated stents were implanted into rabbit carotid arteries to evaluate the inhibitory effects of Fe₃O₄ on neointimal hyperplasia. The major findings of the study were as follows: 1) Fe₃O₄ attenuated neointimal hyperplasia by preventing VSMC proliferation after stenting; 2) Fe₃O₄ exerted inhibitory effects on VSMCs by downregulating proliferative genes such as SOX9, EGR4, and TGFB1, but upregulated inhibitory genes such as DNMT1, TIMP3, and PCNA; 3) Fe₃O₄ inhibited VSMCs by preventing phenotypic transformation from the contractile to the synthetic phase; and 4) Fe₃O₄-coated stents achieved satisfactory hemocompatibility in a rabbit model. Our study highlights the additional benefits of Fe₃O₄ particles in inhibiting VSMC proliferation, indicating that Fe₃O₄ coated stent potentially served as an attractive therapeutic approach for ISR prevention.