Glutathione-Responsive Biodegradable Nanoplatform with Endogenous Esterase-Triggered Nitric Oxide Release for Gas Therapy and Enhanced Chemotherapy

The potential therapeutic effect of nitric oxide (NO) for cancers has received considerable attention as a "killer" that causes damage to mitochondria and DNA by oxidation or nitrosation. However, the fabrication of an intelligent and controllable NO release system has remained elusive in the desired location to realize selective cancer therapy. Herein, an intelligent endogenous esterase-triggered nitric oxide (NO) generator for synergetic cancer therapy is fabricated by integrating NO prodrug and doxorubicin (DOX) into a single glutathione (GSH)-responsive mesoporous silica nanoparticle (MPND). When the MPND is internalized into the cancer cell, the rupture of -S-S- bridges and the degradation of MPND occur in the tumor microenvironment with a high level of GSH, inducing the on-demand release of DOX. Importantly, the high endogenic esterase concentration can activate the prodrug to generate abundant NO, which further enhances the release performance of DOX. In vitro results verify that the release profiles of NO and DOX show the stimuli-responsive dependence of endogenic esterase and GSH, respectively, demonstrating the potential for on-demand release in the cancer cells. Consequently, MPND shows a high antitumor efficiency in MCF-7 cancer cells. Furthermore, using multicellular tumor spheroids to mimic in vivo experiment, MPND can enhance the tumor penetration and therapeutic effect for killing the deep tumor tissue at the central location. Therefore, the endogenous esterase-triggered NO nanogenerators may provide a potential alternative strategy to develop NO-relevant platforms for synergistic cancer therapy.