Glutathione peroxidase mimic-engineered α-lactalbumin self-assembling coatings tailor immunomodulatory vascular stents for suppressing restenosis

Timely endothelial regeneration and repair after stenting is essential for enhancing vascular healing performance. This necessitates that the stent surface be capable of maintaining a positive balance or sequential regulation among thrombosis, inflammation, and the growth behavior of smooth muscle cells (SMCs) and endothelial cells (ECs); however, a key challenge in achieving this goal remains. Herein, we report an immunomodulatory glutathione peroxidase (GPx) mimic-engineered α-lactalbumin self-assembling coating (LASC) for tailoring such surface multi-functionalities of a stent. The coating is achieved by first pre-coating an α-lactalbumin self-assembling nano-film driven by an oxidizing agent onto the stent surface, followed by covalent immobilization of GPx mimics (i.e., Cu^II-tetraazamacrocyclic (Cu-DOTA) coordination complexes) onto the LASC matrix. Cu-DOTA-engineered LASC (Cu-DOTA/LASC) exhibits potent GPx-mimicking catalytic activity, substantially resists adsorption by blood components, and stably and continuously decomposes S-nitrosothiols into nitric oxide (NO) in blood. The long-acting release of NO could create an endothelium-mimicking microenvironment to prevent thrombosis formation, regulate inflammation, inhibit SMC proliferation, and enhance EC growth. As a supplement to the functions of NO, the α-lactalbumin exhibited synergistic effects on anti-thrombosis and immunoregulation. <i>In vivo</i> studies demonstrate that the Cu-DOTA/LASC-functionalized stents enabled rapid re-endothelialization, hence effectively reducing stenosis.