pH-Responsive mineralized nanoparticles as stable nanocarriers for intracellular nitric oxide delivery

S-Nitrosoglutathione (GSNO)-loadedcalcium carbonate (CaCO3)-mineralized nanoparticles (GSNO-MNPs) have been developed for preferential generation of nitric oxide (NO) atendosomal pH and intracellular reducing environments. [Display omitted] ⿢CaCO3-mineralized nanoparticles improve the stability of loaded GSNO in the aqueous phase.⿢CaCO3-mineralized nanoparticles trigger nitric oxide release at intracellular environments.⿢GSNO-loaded mineralized nanoparticlesaugment anticancer activity of doxorubicin. We describe a calcium carbonate (CaCO3) mineralization approach to generate pH-responsive nanocarriers that can stably load S-nitrosoglutathione (GSNO) and dissolve at acidic endosomes to trigger intracellular release of nitric oxide (NO). GSNO-loaded CaCO3-mineralized nanoparticles (GSNO-MNPs) were prepared by an anionic block copolymer (PEG-Poly(l-aspartic acid))-templated mineralization. Ionic GSNO could be loaded in situ inside the CaCO3 core during the mineralization process. The stability of GSNO shielded within the crystalline CaCO3 core was greatly enhanced. The GSNO-MNPs triggered NO release at endosomal pH and an intracellular ascorbic acid level. Confocal microscopy demonstrated that the GSNO-MNPs could be dissolved at endosomal environments to release GSNO and sequentially generate NO through the GSNO reduction in the cytosol. In vitro cell experiments demonstrated that NO release by the GSNO-MNPs efficiently improved therapeutic activity of doxorubicin (DOX).