Summary A wide range of nitric oxide (NO)-releasing materials have emerged as potential therapeutics that exploit NO’s vast biological roles. Macromolecular NO-releasing scaffolds are particularly promising due to their ability to store and deliver larger NO payloads in a more controlled and effective manner compared to low molecular weight NO donors. While a variety of scaffolds (e.g., particles, dendrimers, and polymers/films) have been cleverly designed, the ultimate clinical utility of most NO-releasing macromolecules remains unrealized. Although not wholly predictive of clinical success, in vitro and in vivo investigations have enabled a preliminary evaluation of the therapeutic potential of such materials. Herein, we review the application of macromolecular NO therapies for cardiovascular disease, cancer, bacterial infections, and wound healing.

Cellulose nanomaterials are naturally occurring with unique structural, mechanical and optical properties. While the paper and packaging, automotive, personal care, construction, and textiles industries have recognized cellulose nanomaterials’ potential, we suggest cellulose nanomaterials have great untapped potential in water treatment technologies. In this review, we gather evidence of cellulose nanomaterials’ beneficial role in environmental remediation and membranes for water filtration, including their high surface area-to-volume ratio, low environmental impact, high strength, functionalizability, and sustainability. We make direct comparison between cellulose nanomaterials and carbon nanotubes (CNTs) in terms of physical and chemical properties, production costs, use and disposal in order to show the potential of cellulose nanomaterials as a sustainable replacement for CNTs in water treatment technologies. Finally, we comment on the need for improved communication and collaboration across the myriad industries invested in cellulose nanomaterials production and development to achieve an efficient means to commercialization.

Nitric oxide (NO), a reactive free radical, has proven effective in eradicating bacterial biofilms with reduced risk of fostering antibacterial resistance. Herein, we evaluated the efficacy of NO-releasing silica nanoparticles against Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus biofilms as a function of particle size and shape. Three sizes of NO-releasing silica nanoparticles (i.e., 14, 50, and 150 nm) with identical total NO release (∼0.3 μmol/mg) were utilized to study antibiofilm eradication as a function of size. To observe the role of particle shape on biofilm killing, we varied the aspect ratio of the NO-releasing silica particles from 1 to 8 while maintaining constant particle volume (∼0.02 μm(3)) and NO-release totals (∼0.7 μmol/mg). Nitric oxide-releasing particles with decreased size and increased aspect ratio were more effective against both P. aeruginosa and S. aureus biofilms, with the Gram-negative species exhibiting the greatest susceptibility to NO. To further understand the influence of these nanoparticle properties on NO-mediated antibacterial activity, we visualized intracellular NO concentrations and cell death with confocal microscopy. Smaller NO-releasing particles (14 nm) exhibited better NO delivery and enhanced bacteria killing compared to the larger (50 and 150 nm) particles. Likewise, the rod-like NO-releasing particles proved more effective than spherical particles in delivering NO and inducing greater antibacterial action throughout the biofilm.

A reverse microemulsion synthesis was used to prepare amine functionalized silica nanoparticles of three distinct sizes (i.e., 50, 100, and 200 nm) with identical amine concentrations. The resulting hybrid nanoparticles, consisting of N-(6 aminohexyl) aminopropyltrimethoxysilane and tetraethoxysilane, were highly monodisperse in size. N-diazeniumdiolate nitric oxide (NO) donors were subsequently formed on secondary amines while controlling reaction conditions to keep the total amount of nitric oxide (NO) released constant for each particle size. The bactericidal efficacy of the NO releasing nanoparticles against Pseudomonas aeruginosa increased with decreasing particle size. Additionally, smaller diameter nanoparticles were found to associate with the bacteria at a faster rate and to a greater extent than larger particles. Neither control (non-NO-releasing) nor NO releasing particles exhibited toxicity towards L929 mouse fibroblasts at concentrations above their respective minimum bactericidal concentrations. This study represents the first investigation of the bactericidal efficacy of NO-releasing silica nanoparticles as a function of particle size.

The synthesis of quaternary ammonium (QA)-functionalized silica nanoparticles with and without nitric oxide (NO) release capabilities is described. Glycidyltrialkylammonium chlorides of varied alkyl chain lengths (i.e., methyl, butyl, octyl, and dodecyl) were tethered to the surface of amine-containing silica nanoparticles via a ring-opening reaction. Secondary amines throughout the particle were then functionalized with N-diazeniumdiolates NO donors to yield dual functional nanomaterials with surface QAs and total NO payloads of ca. 0.3 μmol/mg. The bactericidal activities of singly (i.e., only NO-releasing or only QA-functionalized) and dual (i.e., NO-releasing and QA-functionalized) functional nanoparticles were tested against Grampositive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa. Particles with only NO release capabilities alone were found to be more effective against P. aeruginosa, while particles with only QA-functionalities exhibited greater toxicity toward S. aureus. The minimum bactericidal concentrations (MBC) of QA-functionalized particles decreased with increasing alkyl chain length against both microbes tested. Combining NO release and QA-functionalities on the same particle resulted in an increase in bactericidal efficacy against S. aureus; however, no change in activity against P. aeruginosa was observed compared to NO-releasing particles alone.

Despite clear evidence that polymeric nitric oxide (NO) release coatings reduce the foreign body response (FBR) and may thus improve the analytical performance of in vivo continuous glucose monitoring devices when used as sensor membranes, the compatibility of the NO release chemistry with that required for enzymatic glucose sensing remains unclear. Herein, we describe the fabrication and characterization of NO-releasing polyurethane sensor membranes using NO donor-modified silica vehicles embedded within the polymer. In addition to demonstrating tunable NO release as a function of the NO donor silica scaffold and polymer compositions and concentrations, we describe the impact of the NO release vehicle and its release kinetics on glucose sensor performance.

Although the potent anti-tumor activity of nitric oxide (NO) supports its promise as an anti-neoplastic agent, effective and selective delivery and action on tumor and not normal cells remains a limiting factor. Nanoparticle-based delivery of NO has been considered as one approach to overcome these limitations. Therefore, we determined the utility of NO delivery using silica nanoparticles and evaluated their anti-tumor efficacy against human ovarian tumor and nontumor cells. The NO-releasing nanoparticles exhibited enhanced growth inhibition of ovarian tumor cells when compared to both control nanoparticles and a previously reported small molecule NO donor, PYRRO/NO. In addition, the NO-releasing nanoparticles showed greater inhibition of the anchorage-independent growth of tumor-derived and Ras-transformed ovarian cells. Confocal microscopy analysis revealed that fluorescently-labeled NO-releasing nanoparticles entered the cytosol of the cell and localized to late endosomes and lysosomes. Furthermore, we observed a nanoparticle size dependency on efficacy against normal versus transformed ovarian cells. Our study provides the first application of nanoparticle-derived NO as an antitumor therapy and supports the merit for future studies examining nanoparticle formulation for in vivo applications.

Electrospun polyurethane fibers doped with nitric oxide (NO)-releasing silica particles are presented as novel macromolecular scaffolds with prolonged NO-release and high porosity. Fiber diameter (119–614 nm) and mechanical strength (1.7–34.5 MPa of modulus) were varied by altering polyurethane type and concentration, as well as the NO-releasing particle composition, size, and concentration. The resulting NO-releasing electrospun nanofibers exhibited ~83% porosity with flexible plastic or elastomeric behavior. The use of N-diazeniumdiolate- or S-nitrosothiol-modified particles yielded scaffolds exhibiting a wide range of NO release totals and durations (7.5 nmol mg−1–0.12 μmol mg−1 and 7 h to 2 weeks, respectively). The application of NO-releasing porous materials as coating for subcutaneous implants may improve tissue biocompatibility by mitigating the foreign body response and promoting cell integration.