Nitric oxide (NO) is a potent gasotransmitter that exhibits a pleiotropic effect in regulating homeostasis and pathophysiology. Though it is a versatile biomaterial, silicone-based devices are still challenged by implant-associated infections and fibrous capsule formation complications. Here, a NO-generating (NOgen) interface is developed from copper or strontium-doped mesoporous bioactive glass-based coating on silicone substrates to facilitate metal-ion catalysis of endogenous S-nitrosothiols. The copper or strontium-based interfaces can generate physiologically relevant NO levels, which have bactericidal and antithrombotic effects to combat implant-associated early onsite infection and thrombosis. The NO generated in tandem with the low therapeutic release of strontium ions from the NOgen interface regulates cellular fate pertaining to fibroblasts, macrophages, and endothelial cells. Strontium suppresses the collagen expression and migration of activated fibroblasts while favoring M