Influence of Nitric Oxide-Releasing Hyaluronic Acid Form on Immune Modulation

Immune dysregulation, which occurs when the balance of the immune system is compromised, is responsible for many inflammatory and chronic diseases, including those associated with non-resolving infection. Nitric oxide (NO), an endogenous signaling molecule, represents an alternative therapeutic to standard of care interventions as it has the potential to address both chronic infection and inflammation. Hyaluronic acid (HA) is a naturally occurring biopolymer involved in native immune responses, yet its properties as a NO-delivery vehicle can be multifactorial based on its molecular weight. Herein, a library of NO-releasing HA derivatives varying in molecular weight, alkylamine modification, conformation, and NO-release kinetics was synthesized to assess the influence of these properties on biocompatibility and the immunomodulatory activity of macrophages. The NO-release kinetics were dependent on the HA molecular weight, alkylamine modification, and conformation; however, these properties did not influence biocompatibility. All HA derivatives, regardless of their properties, were able to bind to their cognate receptors, but differences in HA properties affected the strength of signaling and macrophage polarization.