Nitric oxide (NO) is a potent biological molecule that contributes to a wide spectrum of physiological systems, including cardiovascular system, immune system, central nervous system, and outflow physiology. However, NO delivery technology remains severely limited due to the physiological properties of NO: 1) NO has a short half-life in human tissues (seconds); 2) NO can only diffuse over short distances (~100 µm), thus limiting its action to only areas near the source of delivery; and 3) NO can exert protective or deleterious effects depending on its concentration. Current strategies for NO delivery focus on encapsulation of NO donors into pre-fabricated scaffolds or an enzyme-prodrug therapy approach. The former is limited by the finite pool of NO donors available, while the latter is challenged by the inherent low stability of natural enzymes. Enzyme mimics are attractive substitutes for their natural counterparts in diverse biomedical applications because they have excellent stability against biological degradation, high temperature, and extreme pH conditions compared with natural enzymes. In this work, we present nanoparticles with innate glutathione peroxidase and glycosidase activities that catalytically decompose endogenous and exogenous NO donors (e.g. S-nitrosoglutathione, S-nitrosocysteine, and β-gal-NONOate) to generate NO at physiological conditions. Through the nanozyme approach, we envision that sustained NO delivery could be achieved by relying on life-long pools of endogenous NO donors, and when needed, on-demand NO delivery at the desired levels of NO could be realized by externally administered exogenous NO prodrugs. By tuning the concentrations of particles and NO prodrugs, physiologically relevant NO levels were generated. These materials preserved their catalytic property to generate NO for at least 6 months. We further demonstrated the therapeutic activity of NO generated by nanozymes to inhibit cancer cell proliferation and to disperse bacterial biofilms. Our findings may open new routes to the next generation of NO-releasing biomaterials and devices in diverse biomedical applications.

Nanozymes for nitric oxide delivery from endogenous and exogenous prodrugs

ACS Spring 2022

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