Fructose‐coated Ångstrom silver particles suppress gastric cancer growth by activating gasdermin D‐mediated pyroptosis

Gastric cancer (GC) remains an important cancer worldwide, ranking fifth for incidence and fourth for mortality globally. Surgery combined with chemotherapy is recognized as a curative regimen for GC. However, much safer and more effective methods should be developed to improve the survival rate. Formerly, a pure physical method is presented to prepare Angstrom-scale silver particles (AgAPs) and anticancer effects of fructose-coated AgAPs (F-AgAPs) are found. In this research, the efficacy and alternative pyroptosis induction of F-AgAPs in the treatment of GC are investigated and compared with those of cisplatin in subcutaneous GC tumor-bearing nude mice. F-AgAPs inhibit GC cell growth, promote lactate dehydrogenase (LDH) release, and induce cell pyroptosis in vitro. The caspase-1 selective inhibitor belnacasan (VX-765) and the pyroptotic pore formation inhibitor necrosulfonamide (NSA) partially reverse F-AgAP-induced pyroptosis in GC cells. In vivo, F-AgAPs significantly upregulate inflammasome formation, caspase-1 expression, and gasdermin D (GSDMD) cleavage, thus inducing pyroptosis. Furthermore, intravenous and oral administrations of F-AgAPs do not induce any obvious toxicities in healthy tissues. This study indicates that GSDMD-dependent pyroptosis is a novel mechanism by which F-AgAPs protect against GC in vitro and in vivo, which may provide a new therapeutic strategy for anti-GC treatment.