Immuno-resolving nitric oxide-generating stents for coordinated vascular healing

Delayed endothelialization and persistent inflammation remain key challenges for long-term vascular healing after stent implantation. Here, we develop a temporally coordinated immunoregenerative coating (C15-NOGC) that couples sustained nitric oxide (NO) generation with C15-associated immunomodulation. The coating is fabricated via in situ re-crosslinking of Cu-DOTA-modified polyamine within a polydopamine coating, followed by bioorthogonal immobilization of the pro-resolving peptide chemerin-15 (C15), yielding a mechanically robust interface with stable peptide presentation and physiological-level NO release. Functionally, immobilized C15 promotes a pro-resolving macrophage phenotype associated with increased ChemR23 expression, enhances phagocytic activity, and reduces pro-inflammatory responses. Concurrently, continuous NO generation provides antithrombotic activity, promotes endothelial regeneration, and modulates smooth muscle cell phenotype and vascular remodeling. Following stent implantation in ApoE^-/- rats, C15-NOGC significantly enhances early re-endothelialization, is associated with a reduced neointimal area, and shows favorable local vascular remodeling responses compared with bare metal and drug-eluting stents. PCR-array and proteomic analyses further reveal complementary molecular signatures associated with inflammatory regulation, vascular remodeling, and reparative processes, providing molecular context for the observed vascular responses. Together, these findings support a temporally coordinated strategy that integrates C15-associated immunomodulation with endothelial-mimetic NO generation for pro-healing vascular stent design.