A Time-Sequenced Three-Drug-Loaded Microneedle Patch for the Prevention of Vein Graft Restenosis After Coronary Artery Bypass Grafting

Coronary artery bypass grafting (CABG) is the recommended treatment for severe coronary heart disease; however, restenosis of great saphenous vein grafts continues to limit long-term outcomes because of early thrombosis, mid-term intimal hyperplasia, and late atherosclerosis. To address these sequential pathological processes, this study develops a perivascular drug-loaded microneedle (MN) patch capable of controlled chronological release of tirofiban, rapamycin, and rosuvastatin. The MN patch exhibits uniform conical microneedles (height: 700–800 µm), nanoparticle size of 125 nm, sufficient mechanical strength (1.07 N/needle) for venous intimal penetration, excellent biocompatibility, and no detectable cytotoxicity or hemolysis. In a mouse model of venous graft transplantation, the device significantly reduces early platelet thrombus formation (23.3% to 10%), alleviates mid-term intimal hyperplasia (intimal thickness: 0.84 mm to 0.45 mm at 4 weeks), and improves long-term graft patency with blood flow increasing from 13.1 to 65.8 mL/min at 32 weeks while reducing long-term mortality. Mechanistically, RNA sequencing and functional analyses demonstrate that excessive glycolysis-driven smooth muscle cell proliferation, coupled with abnormal endothelial cell apoptosis, constitutes the core mechanism underlying mid- to long-term restenosis, which the MN device effectively suppresses. This integrated MN patch provides a localised therapeutic strategy for preventing restenosis and improving long-term CABG outcomes.