Nitric-Oxide-Modulatory Materials for Biomedical Applications

CONSPECTUS: Nitric oxide (NO) is an endogenous signaling molecule that participates in various physiological and biological pathways associated with vasodilation, immune response, and cell apoptosis. Interestingly, NO has versatile and distinct functions in vivo depending on its concentration and the duration of exposure; it aids cellular proliferation at nanomolar concentrations but causes cellular death at micromolar concentrations. Therefore, achieving the precise and on-demand modulation of microenvironmental NO concentrations has become a major research target in biomedical fields. To this end, many studies have investigated feasible means for developing functional moieties that can either exogenously donate or selectively scavenge NO. However, these advances are limited by poor stability and a lack of target specificity, which represent two significant obstacles regarding the spatiotemporal adjustment of NO in vivo. Our group has addressed this issue by contributing to the development of next-generation NO-modulatory materials over the past decade. Over this period, we utilized various polymeric, inorganic, and hybrid systems to enhance the bioavailability of traditional NO donors or scavengers in an attempt to maximize their clinical usage while also minimizing their unwanted side effects. In this Account, strategies regarding the rational design of NO-modulatory materials are first summarized and discussed, depending on their specific purposes. These strategies include chemical approaches for encapsulating traditional NO donors inside specific vehicles; this prevents spontaneous NO release and allows said donors to be exposed ondemand, under a certain stimulus. The current status of these approaches and the recent contributions of other groups are also comprehensively discussed here to ensure an objective understanding of the topic. Moreover, in this paper, we discuss strategies for the selective depletion of NO from local inflammatory sites, where the overproduction of NO is problematic. Finally, the major challenges for current NO-modulatory systems are discussed, and requirements are outlined that need to be tackled to achieve their future therapeutic development. Starting from this current, relatively early stage of development, we propose that, through continuous efforts to surmount existing challenges, it will be possible in the future to achieve clinical translations regarding NOmodulatory systems. This Account provides insightful guidelines regarding the rational design of NO-modulatory systems for various biomedical applications. Moreover, it can facilitate the achievement of previously unattainable goals while revolutionizing future therapeutics.