Dual-Mode Nitric Oxide Releasing Vascular Grafts for Vascular Homeostasis and Antibacterial Defense.

Thrombosis, restenosis, and infection remain persistent challenges for vascular grafts, often leading to graft failure and severe clinical consequences. However, existing solutions are often limited by compromised functionality or impractical manufacturing complexity. Inspired by the spatiotemporal nitric oxide (NO) release patterns of endothelial (eNOS) and inducible (iNOS) synthases in native vasculature, we propose a dual-mode NO release strategy. Through facile incorporation of BNN6, a photoresponsive N-nitrosamine NO donor, into electrospun polycaprolactone (PCL), the graft achieves sustained eNOS-like NO release comparable to that of native endothelium, along with light-triggered iNOS-mimicking bursts for rapid bacterial eradication. The resulting PCL/BNN6 grafts exhibit tunable and long-lasting NO-releasing behavior. In vitro, eNOS-like NO release effectively suppresses platelet activation, inhibits smooth muscle cell adhesion, proliferation, and migration, and promotes macrophage polarization toward an anti-inflammatory phenotype. Upon light activation, iNOS-mimicking NO bursts efficiently eliminate both S. aureus and E. coli. In vivo, the grafts significantly attenuate inflammatory responses, and their light-activated antibacterial capability is validated in a simulated infection model. Overall, this bioinspired dual-mode NO release strategy establishes a dynamic interface between graft functionality and physiological demands, offering a promising solution to the multifactorial complications of vascular grafts through spatiotemporally controlled NO delivery. STATEMENT OF SIGNIFICANCE: Vascular grafts frequently fail due to thrombosis, restenosis, and bacterial infection. While nitric oxide (NO) plays a central role in preventing these complications, most NO-releasing materials suffer from short-lived or poorly controlled release. This study presents an eNOS/iNOS-inspired dual-mode NO-releasing graft that mimics native NO regulation-providing sustained baseline release for vascular homeostasis and light-triggered bursts for antibacterial defense. The system couples ease of fabrication with robust in vitro and in vivo performance, integrating antithrombotic, anti-hyperplastic, and antibacterial functions into a single platform. This work offers a promising strategy to enhance the long-term success of vascular implants and may inform future development of smart, responsive biomaterials.