We report the synthesis of S-nitrosothiol-modified silica particles capable of nitric oxide (NO) release. The thiol precursor modification to form S-nitrosothiol NO donors was introduced into the silica network via co-condensation of mercaptosilane and alkoxysilane precursors. Both the concentrations of reactants (i.e., water, ammonia, and silane) and the silane feed rate into the reaction proved important in the yield of monodisperse, spherical particles with tunable diameters ranging from 241-718 nm. Subsequent nitrosation resulted in NO storage approaching ~4.40 μmol NO mg(-1), as determined by total NO release. Behaving similar to low molecular weight S-nitrosothiol NO donors, the NO release from the macromolecular silica vehicles was influenced by light, temperature, and metal ions.