Nitric oxide-modulating biomaterials for therapeutic Immunoengineering

Abstract

Nitric oxide (NO) plays dual and context-dependent roles in the immune system, functioning as either an immunostimulatory or immunosuppressive mediator depending on its concentration, cellular source, and exposure dynamics. Dysregulated endogenous NO production is implicated in the pathogenesis of a broad spectrum of diseases. Therapeutic modulation of NO levels via engineered delivery systems represents a promising approach for immune regulation. This review provides a comprehensive overview of NO-modulating biomaterials, with a focus on two opposing strategies: NO scavenging to remove pathologically excessive NO and NO delivery to restore physiologically essential NO levels. We first examined the distinct molecular mechanisms and cell type-specific effects of endogenous and exogenous NO, highlighting its pleiotropic immunoregulatory roles in macrophages, dendritic cells, T cells, B cells, neutrophils, and myeloid-derived suppressor cells. We then classify representative NO scavengers and NO donors according to their chemical structures and activation triggers, including pH, redox, enzyme, and stimulus-responsive systems. Next, we discuss the design and application of advanced biomaterial-based platforms that integrate these agents into immunoengineering interventions for various disease models. Finally, we address the key translational challenges and design principles required to achieve precise, spatiotemporally controlled, and disease-selective NO modulation. Collectively, this review summarizes recent advances in NO-regulating biomaterials and highlights their potential to reprogram immune responses for therapeutic benefit.